Open access peer-reviewed chapter

Mesenchymal Stromal Cells as a Therapeutic Intervention

Written By

Ivonne Hernandez Schulman and Joshua M. Hare

Submitted: December 6th, 2017 Reviewed: May 10th, 2018 Published: November 5th, 2018

DOI: 10.5772/intechopen.78586

Chapter metrics overview

1,430 Chapter Downloads

View Full Metrics

Abstract

Mesenchymal stem cells, also known as mesenchymal stromal cells (MSCs), are a safe and promising biologic therapeutic for inducing tissue repair and regeneration in a broad array of chronic diseases. The mechanisms underlying the beneficial effects of MSCs include immunomodulation, reduction in inflammation and fibrosis, and stimulation of neovascularization and endogenous regeneration. Accumulating evidence from a multitude of clinical trials support the notion that both autologous and allogeneic MSCs are not only safe but also possess the capacity for repair of diverse organ systems and amelioration of multiple chronic disease processes. However, there are many questions regarding the underlying mechanisms of action, the most efficacious cell characteristics, tissue source, dose/concentration, route of delivery, and timing of administration, interactions with concurrent therapies, sustainability of effect, donor and patient characteristics, and adverse effects, including infections and malignancy, that remain to be resolved. Answering these questions will require well-designed and rigorously conducted multicenter clinical trials with well-established and defined clinical endpoints and appropriately defined patient populations, number of patients, and duration of follow-up. This chapter will review the current state of knowledge in the use of MSCs as a therapeutic strategy for organ structural and functional repair in chronic diseases.

Keywords

  • cell transplantation
  • mesenchymal stem cells
  • regenerative medicine

1. Introduction

Mesenchymal stem cells (a.k.a. mesenchymal stromal cells, MSCs) hold enormous promise as a durable, sustainable, and novel cell-based biologic therapeutic for a diverse range of clinical applications aimed at preventing or reversing organ injury and promoting tissue regeneration. Substantial data have accumulated regarding the safety of administering both autologous and allogeneic MSCs to patients with a broad array of diseases. In addition, it is increasingly clear that MSCs exert anti-fibrotic, pro-angiogenic, regenerative, and immunomodulatory effects, and therefore, offering therapeutic potential in a wide range of presently untreatable conditions. The growing evidence supporting the use of MSCs as therapeutic strategy includes their relative ease of isolation and expansion in culture, multilineage differentiation capacity, immunomodulatory, anti-inflammatory, anti-microbial, and regenerative effects, homing and migratory capacity to injury sites, safety profile in allogeneic transplantation, and few ethical considerations [1, 2]. The use of large animal models in preclinical studies has been instrumental in deciphering the underlying mechanisms of action of MSC therapy [3]. Moreover, substantial human phenotypic data has demonstrated that MSC therapy is safe [4, 5, 6, 7, 8, 9, 10] and holds the potential for repair and regeneration of diverse organ systems and amelioration of multiple chronic illnesses for which there is currently no cure [4, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24]. There are currently various MSC sources under investigation in preclinical and clinical studies, namely bone marrow, adipose tissue, umbilical cord blood, umbilical cord, and amniotic membranes/placenta (Figure 1). Multiple mechanisms of action underlie successful MSC therapy, including MSC engraftment and differentiation, and more importantly, the secretion of bioactive paracrine molecules that inhibit apoptosis, fibrosis, and inflammation and promote neovascularization/neo-angiogenesis and endogenous stem cell recruitment, proliferation, and differentiation [25, 26, 27] (Figure 2). In particular, cell-cell interactions between MSCs and endogenous host cells within stem cell niches provide structural support and produce the soluble signals that regulate stem cell function in tissues[1, 28, 29, 30] (Figure 1 inset). An in-depth molecular understanding of how MSCs produce the therapeutic benefits demonstrated in numerous clinical trials is critical for the development and design of new clinical trials as well as for the development of newer generations of MSC products that have greater efficacy and sustainability. This chapter will review the current state of knowledge in the use of MSCs as a therapeutic strategy for organ structural and functional repair.

Figure 1.

Mesenchymal stem cell tissue sources, ex vivo expansion, and role in stem cell niche. Initially identified in bone marrow, MSCs can be isolated from various tissues in the body. To isolate MSCs from a bone marrow biopsy, first the mononuclear cells are isolated from red blood cells by Ficoll density centrifugation, and subsequently, the MSCs are separated from the mononuclear cells by plastic adherence in culture. Inset: the constituents of a stem cell niche are depicted in this schematic. ECM extracellular matrix.Adapted from Wagers AJ et al., Cell Stem Cell, 2012.

Figure 2.

Mechanism of action of mesenchymal stem cell therapy.

Advertisement

2. Biology of mesenchymal stem cells

MSCs are non-hematopoietic stem cells with multilineage potential that originate from the mesodermal germ layer. The pioneering studies conducted by Friedenstein et al. provided the first evidence that these fibroblast-like cells, described as spindle-shaped and clonogenic in culture conditions could be isolated from bone marrow via their inherent adherence to plastic in culture [31, 32]. MSCs are an integral part of the stromal microenvironment and support hematopoietic stem cells and regulate hematopoiesis, although they comprise only ~0.01–0.001% of the total nucleated cells in the bone marrow [33, 34]. Moreover, MSCs have been isolated from virtually every tissue type, including adipose tissue, liver, lung, skeletal and heart muscle, synovial membrane, amniotic fluid, placenta, umbilical cord blood, and dental pulp, suggesting that they reside in all organs [35, 36, 37].

MSCs are readily expanded in vitroand have the capacity, as classically defined, to differentiate into osteoblasts, chondrocytes, and adipocytes [38, 39]. Studies also strongly support a role for MSCs in neovascularization, with the capacity for differentiation into both endothelial [40, 41] and vascular smooth muscle cells [40]. Finally, MSCs can differentiate into myocytes: skeletal myocyte differentiation is widely accepted, whereas there is ongoing controversy as to whether MSCs have a robust ability to form cardiomyocytes [40, 42, 43, 44, 45].

No single cell surface marker specifically identifies MSCs. The International Society for Cellular Therapy has provided minimum criteria for defining multipotent human MSCs including (1) plastic-adherence under standard culture conditions; (2) expression of CD105, CD73, and CD90 and absence of hematopoietic cell surface markers, CD34, CD45, CD11a, CD19, and HLA-DR; and (3) in vitrodifferentiation into osteocytes, adipocytes, and chondrocytes under specific culture conditions [46]. However, MSCs can lose/acquire surface markers as they are isolated and expanded [47]. Furthermore, MSCs isolated from different tissues may exhibit a molecular fingerprint specific for their tissue of origin and thus vary in their differentiation capacity [48, 49, 50].

Bone marrow-derived MSC precursors (MPCs) have also been identified based upon specific cell surface marker expression, the most important being stromal precursor antigens (STRO-1, STRO-3) and CD271 [51, 52, 53, 54, 55, 56]. In vitrostudies suggest that the STRO-1 and STRO-3-enriched MPC populations have superior proliferative ability, multilineage regenerative capacity, and paracrine activity compared to MSCs [51, 54, 55], whereas CD271+ selection significantly increases clonogenic outgrowth of MPCs [52]. Preclinical studies using large animals have shown the efficacy of MPCs in acute MI and chronic ischemic and non-ischemic models of cardiomyopathy. Intracoronary injection of allogeneic MPCs in sheep after acute MI produced a 40% decrease in scar size and a 50% increase in vascular density [57]. Similarly, using echocardiography to guide the catheter-based endomyocardial injection of allogeneic MPCs into sheep 4 weeks post-MI resulted in an increase in left ventricular ejection fraction (LVEF), wall thickness, and vascular density. In a model of non-ischemic cardiomyopathy, transendocardial administration of ovine allogeneic cells produced decreased left ventricular end-systolic volume, stabilization of LVEF, decreased myocardial fibrosis and increased myocardial regeneration [53].

2.1. Osteogenic, chondrogenic, and adipogenic differentiation

As mentioned above, MSCs can be readily expanded in vitroand can differentiate into osteoblasts, chondrocytes, and adipocytes [38, 39]. Various growth factors and molecules promote MSC differentiation. For instance, global gene expression profiling arrays were utilized to identify RNA transcripts, which led to the identification that TGF-β, platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) signaling pathways regulate MSC differentiation into adipogenic, osteogenic, and chondrogenic lineages [58, 59]. Adipogenic and osteogenic differentiation of MSCs were enhanced in vitroupon inhibition of TGF-β signaling but prevented chondrogenic differentiation. In contrast, inhibition of PDGF signaling decreased osteogenic differentiation, whereas inhibition of FGF receptor signaling completely blocked osteogenic differentiation and reduced chondrogenic differentiation. Moreover, inhibition of any one of these pathways decreased MSC proliferation. Differentiation thus depends substantially on the microenvironment [60].

A key question regarding postnatal MSC function is the degree to which they participate in tissue homeostasis. For example, in the case of an osteogenic lineage, multiple investigators [61, 62, 63] have shown that exposure of MSCs to dexamethasone, β-glycerol phosphate, and ascorbic acid can lead to expression of alkaline phosphatase by the differentiated osteogenic cells with subsequent formation of a mineralized extracellular matrix [61]. Importantly, MSCs do retain the capacity for bone differentiation in vivo [38, 64]. For example, we have shown that subcutaneously implanting MSCs leads to osteoblast differentiation [38]. On the other hand, chondrogenic differentiation of MSCs can be achieved by treating MSCs with dexamethasone and TGF-β3 [58]. Similarly, dexamethasone together with insulin, indomethacin, and 1-methyl-3-isobutylxanthine can stimulate MSC differentiation into adipocytes, which express adipocyte-specific markers including peroxisome proliferator-activated receptor (PPAR)-γ [65].

Cao et al. [38] studied the regulation of MSC differentiation into adipocytes and osteoblasts with relation to PPAR-γ, an essential checkpoint regulator of the “adipogenesis-osteogenesis balance.” The study showed that S-nitrosoglutathione reductase (GSNOR)-deficient mice have reduced adipogenesis and increased osteoblastogenesis compared to normal mice (Figure 3). Notably, GSNOR MSCs had improved differentiation capacity for bone and reduced propensity for adipocytes. This is due to higher levels of S-nitrosylated PPAR-γ protein with subsequent inhibition of its transcriptional activity, suggesting a negative feedback regulation by NO-mediated S-nitrosylation. In addition, S-nitrosylation of PPAR-y inhibits binding affinity to its downstream target fatty acid-binding protein 4 (FABP4) promoters (Figure 4). Importantly, the MSC differentiation affected the phenotype on the whole animal level. GSNOR deficient mice have lower body weight and fat mass, accompanied by elevated bone formation. In another study regarding osteogenic regulation, investigators found that modulation of specific microRNAs (-148b, -27a, and -489) plays a crucial role in MSC early osteogenic differentiation [66]. This has a tremendous corollary in bone diseases such as osteoporosis by providing both pathophysiological and therapeutic insights. Indeed, MSC differentiation into other cell lines of mesenchymal origin can offer further understanding into many other human disease processes, in support of future treatment strategies.

Figure 3.

GSNOR deficient mice have reduced weight and body mass with increased bone formation.

Figure 4.

Regulation of adipogenesis-osteogenesis by MSCs. GSNOR deficiency with ensuing elevated levels of S-nitrosylated PPAR-γ leads to a decrease in PPAR- γ transcriptional activity and binding affinity to FABP4 promoter. This results in increased osteogenesis and decreased adipogenesis, which has strong implications in bone disease.Reproduced from Cao Y et al., JCI, 2015.

2.2. Cardiac differentiation

Cardiomyogenic differentiation of MSCs is of key interest for cardiac regenerative medicine, particularly ischemic and non-ischemic cardiomyopathy [40, 67, 68]. Treating MSCs with 5-azacytidine produces spontaneous, synchronous beating cells in culture with ventricular myocyte-like potentials, suggesting that MSCs are able to transdifferentiate into cardiomyocytes [43]. Alternative and potentially safer factors that induce differentiation into a cardiomyocyte phenotype include conditioned media containing bone morphogenetic protein-2 (BMP-2) and FGF-4 [69] as well as insulin, dexamethasone, and ascorbic acid [70]. The combination of these factors induces overexpression of cardiomyocyte-specific proteins, leading to cardiomyogenic differentiation for possible use in disease processes of injured myocardium [69, 70, 71, 72]. Indeed, expression of myotubules, α-actinin, SERCA2 and other cardiac-related proteins in transdifferentiated cells may serve to attenuate cardiac infarct size and enhance perfusion, and regional function as suggested by early in vivostudies [73, 74]. Co-culture of mouse or rat MSCs with rat neonatal ventricular myocytes also stimulates MSC transdifferentiation into cardiomyocytes [75, 76]. The necessity of cell-to-cell contact [1, 75] versus secreted factors within the cardiac microenvironment [76] as a requirement for cardiomyogenic differentiation remains unclear.

MSC therapy promotes cardiomyogenesis not only by direct cardiomyocyte differentiation, but also by stimulating endogenous c-kit+ cardiac progenitors (CPCs) to proliferate, undergo lineage commitment, and form transient amplifying cells [1, 28, 29, 77, 78, 79]. We demonstrated that transendocardial injections of allogeneic MSCs in swine following myocardial infarction (MI) results in cardiogenic differentiation of MSCs accompanied by increased proliferation and enhanced lineage commitment of endogenous CPCs, and reconstitution of niche-like structures [1]. This stimulation of endogenous CPCs by MSCs requires a complex molecular interaction and is a crucial component of the beneficial cell therapeutic effects [1, 28, 29, 77, 78, 79]. Histologic examination revealed chimeric clusters (niches) comprised of adult cardiomyocytes, transplanted MSCs and CPCs expressing connexin-43 gap junctions, and N-cadherin mechanical connections between cells. These findings support the notion that MSCs act both as progenitors for certain cell lineages and through their participation in niches, as supporting cells for other lineages [80].

Stimulation of endogenous precursors may be a general mechanism underlying MSC bioactivity. We recently showed that in humans with endothelial dysfunction MSCs can trigger endogenous EPC activation increasing their number and functional quality [81]. Thus MSCs can serve as a powerful therapeutic tool by reconstituting endogenous stem cell niches as well as enabling and augmenting the reparative abilities of endogenous stem cells.

2.3. Anti-fibrotic and proangiogenic effects

The hypothesis that exogenously delivered stem cells would promote organ regeneration through transdifferentiation into tissue-specific cells sparked interest in stem cell research and cell-based therapy and was originally supported by studies in the heart [82] where MSCs become cardiomyocyte-like cells and endothelial cells [40, 41, 43]. However, subsequent studies have revealed that the MSC-mediated regenerative process is more complex than was initially envisioned, and that several mechanisms underlie the ability of MSCs to reduce scar size and improve left ventricular structure and function after myocardial injury [33, 83, 84]. MSCs engraft and persist for several months in myocardium when delivered by transendocardial injection [1, 33, 40] and they reduce cardiac fibrosis and promote neovascularization and cardiomyogenesis [40, 77, 85, 86]. Importantly, cardiac magnetic resonance imaging (MRI) documented a reduction of infarct size, improvement in left ventricular shape (measured as sphericity index of the left ventricle), and improvement in tissue perfusion and regional contractility [87]. Together, these preclinical studies support the anti-fibrotic and proangiogenic role of MSCs in the repair of the injured myocardium.

2.4. Immunomodulatory, anti-inflammatory, and anti-microbial effects

Preclinical studies have demonstrated that MSCs can differentiate into cardiomyocytes and/or vascular structures in both allogeneic [1, 40, 87] and xenotransplantation [88] models, contributing to cardiac functional improvement and reduction of infarct size. Remarkably, there has been no evidence of rejection in animals subjected to allogeneic transplantation of MSCs [1, 29, 40, 87]. These studies reveal that allogeneic MSCs represent a unique cell population for cellular therapy due to their anti-proliferative, immunomodulatory, and anti-inflammatory effects [2, 33, 89]. The absence of major histocompatibility class (MHC) II antigens [90, 91, 92] and the secretion of T helper type 2 cytokines characterize MSCs as both immunoprivileged and immunosuppressive [2, 92, 93, 94]. MSCs fail to induce proliferation of allogeneic lymphocytes in vitro[90, 92], and suppress proliferation of T cells activated by allogeneic cells or mitogens [91]. This immunomodulatory capacity supports the feasibility of using allogeneic MSCs for cardiovascular regeneration as well as other clinical applications [2, 95]. Furthermore, MSCs have been used to treat severe graft-vs-host disease (GVHD) [13, 96], decreasing the potential of graft rejection and/or GVHD, and supporting the concept that MSCs are a unique cell population for regenerative medicine with minimal immune reactivity. Allogeneic MSCs have proven both safe and effective [5, 7, 11, 29, 89], highlighting that MSCs engrafted in the cardiac tissue despite potential HLA mismatching. An advantage of allogeneic MSCs is their potential use as an “off-the-shelf” therapeutic agent, precluding the need to obtain and expand bone marrow or another tissue source from the patient, and providing consistency to the cell product [97]. In addition, autologous cells may have functional deficiencies due to the underlying diseases, co-morbidities, lifestyle, concomitant medications, or age [98, 99, 100, 101, 102, 103, 104, 105]. Although allogeneic MSCs may be cleared more rapidly than autologous cells after differentiation [106], immunologic clearance might also offer the advantage of reducing any long-term risks of cell implantation [8, 94, 107].

An important concern, and common exclusion criteria for participation in clinical trials is that the potential immunosuppressive effect of MSCs may lead to an increased risk of infection in patients who are already immunosuppressed due to medical therapy or concurrent chronic disease. In this regard, recent data has shown that MSCs exert significant anti-microbial effects through both direct and indirect mechanisms [108]. Indirect mechanisms include regulation of macrophages, neutrophils, phagocytes, and another pro- and anti-inflammatory cells of the immune system, whereas indirect mechanisms involve the secretion of anti-microbial peptides and proteins (AMPs) and the expression of indoleamine 2,3-dioxygenase, interleukin-17, and other molecules [94, 108]. Indeed, the anti-microbial effects of MSCs have been demonstrated in preclinical studies of sepsis, acute respiratory distress syndrome, and cystic fibrosis-related infections [108].

2.5. Enhancement of MSC therapy

Therapeutic interventions to optimize MSC function, such as growth factor administration [109, 110, 111, 112], gene therapy [110], and modulation with small molecules or other pharmacologic approaches [110] are promising options under preclinical and clinical investigation to potentiate myocardial repair and regenerative capacity. For example, in the phase I cardiopoietic stem cell therapy in heart failure (C-CURE) trial and subsequent phase II/III congestive heart failure cardiopoietic regenerative therapy (CHART-1) study [72, 109, 113], autologous bone marrow-derived MSCs from patients with ischemic cardiomyopathy were treated ex-vivo with a cardiogenic cytokine cocktail to enhance their cardiac lineage commitment. In C-CURE, the authors reported significant improvement in cardiac function, physical performance, hospitalization, and event-free survival in the cell therapy group compared to controls [109]. However, the larger CHART-1 trial reported neutral results at 39 weeks of follow up with regards to composite and individual outcomes, including all-cause mortality, heart failure events, and surrogate cardiac structural and functional endpoints [113]. A sub-analysis of the CHART-1 study extended the follow-up period to 52 weeks at which point the anti-remodeling properties of the cardiopoietic MSCs became evident [72]. These findings are consistent with those of other clinical trials of MSC-based therapy for ischemic cardiomyopathy [7, 9, 114].

A potential approach to improve therapeutic potential is the combination of MSCs with c-kit+ CSCs [28, 29, 79]. Using a porcine model of chronic ischemic cardiomyopathy, the combination of autologous or allogeneic swine MSCs and c-kit+ CSCs provides greater reverse remodeling, scar size reduction, and functional improvements than MSCs alone [29, 79]. The demonstrated safety of cell-based therapy using MSCs [7, 9, 115, 116] and c-kit+ CSCs [117, 118] in patients with ischemic cardiomyopathy combined with these preclinical findings revealed important biological interactions between these two stem cell types that enhance therapeutic responses and led to the initiation of the Cardiovascular Cell Therapy Research Network (CCTRN)-sponsored, Combination of Mesenchymal and C-kit+ Cardiac Stem Cells as Regenerative Therapy for Heart Failure (CONCERT-HF; NCT02501811) clinical trial.

2.6. MSC senescence and potential malignant transformation

There is evidence that senescence impairs the capacity of MSCs for multi-lineage differentiation, homing, immune modulation and wound healing [102, 103]. As stem cells age, they undergo a “quiescence-to-senescence switch” that impairs their function [102, 104, 119, 120] (Figure 5). The mechanisms underlying the age-related declines in stem cell function involve intrinsic aging as well as age-related changes in their tissue microenvironment, including extracellular matrix components and the stem cell niche [101, 104, 121], thereby adversely impacting self-renewal and therapeutic potential. This has implications when considering the age and comorbidities of patients and donors. For example, dysfunctional stem cell niches have been implicated in the aging frailty syndrome, which is characterized by decreased strength, endurance, physiologic function, and reserve capacity in multiple organ systems [122, 123]. Moreover, aging, renal failure, C-reactive protein (CRP) levels, and other adverse health parameters have been shown to correlate significantly with poor angiogenic potency of bone marrow stem cells [105, 124]. These studies suggest that the therapeutic potential of autologous MSCs obtained from patients may be limited, whereas more robust repair and regeneration would occur by using allogeneic MSCs from young, healthy donors. Indeed, two clinical trials in patients with ischemic and dilated cardiomyopathy, respectively, compared autologous to allogeneic MSCs and found that although both provided benefits in cardiac structural endpoints, the allogeneic MSCs provided greater cardiovascular functional benefits [5, 7, 81]. On the other hand, a study on the impact of recipient age on the efficacy of MSC therapy found that older (>60 years of age) patients responded just as effectively as younger (<60 years of age) patients when administered either autologous or allogeneic MSC therapy for chronic ischemic cardiomyopathy [125]. This finding is highly significant since the majority of the population with cardiovascular disease requiring cell-based therapy is aged.

Figure 5.

Proposed mechanisms of aging-induced stem cell dysfunction. (A). Normal stem cell function involves activation of a quiescent stem cell to divide asymmetrically giving rise to a new stem cell (self-renewal) and another daughter cell that undergoes proliferation and differentiation. (B). Failure of self-renewal involves differentiation of both daughter cells, leading to a gradual depletion of the stem cell pool. (C). Aberrant differentiation may result from the abnormal skewing of the distribution of progeny toward one fate instead of various potential fates. Another potential mechanism involves the daughter cells acquiring abnormal fates that are not part of the normal repertoire. (D). Impaired stem cell response may be due to a decline or impairment in extrinsic or intrinsic signals. (E). Senescence and apoptosis of the quiescent stem cell or among the progeny following activation has also been described in aging. Adapted from Jones DL et al., Nature Cell Biology, 2011.

Although the evidence is conflicting [126, 127, 128, 129, 130], clinical trials of MSC therapy usually exclude patients with a history of cancer due to concerns regarding the MSCs’ potential for carcinogenesis. It remains unclear whether MSCs have the potential to undergo spontaneous malignant transformation and/or whether they interact with surrounding tumor stromal elements [129, 130, 131]. Spontaneous malignant transformation of human bone marrow-derived MSCs has been shown in vitro during long-term cultures [127]. These MSCs underwent faster proliferation, failed to undergo complete differentiation, and exhibited altered morphology and phenotype. Moreover, when these altered MSCs were administered to immunodeficient mice rapid-growing tumors throughout the lung tissue were found. On the other hand, in a separate study [128], human bone marrow-derived MSCs were grown in culture and assessed at different time points for expression of various tumor-related proteins until they reached senescence or passage 25. A progressive decrease in proliferative capacity with shortened telomeres was observed in most cultured MSCs until they reached senescence. In addition, the MSCs did not express telomerase activity or telomerase reverse transcriptase transcripts, and no chromosomal abnormalities or alternative lengthening of telomeres were observed, supporting the safety of in vitro MSC expansion, and therapeutic use. Despite these encouraging findings, the functional, phenotypic, and genetic characterization of culture-expanded MSCs merits further careful study [129, 131, 132]. In addition, recent findings indicate that various direct (e.g., cell fusion) and indirect (e.g., exosome or vesicle-mediated) interactions between MSCs and cancer cells can produce functional interference and/or mutual acquisition of new cellular properties [130]. These functional and phenotypic cellular alterations can lead to changes in metastatic behavior and induce new cancer stem cell development. On the other hand, exosomes and vesicle-mediated mechanisms may be a promising therapeutic tool against cancer.

2.7. Sex differences in MSCs

Sex differences exist in many disease states as well as with respect to the role of MSCs in organ repair and regeneration after injury. There is evidence that female MSCs exhibit decreased apoptosis, interleukin-6, and tumor necrosis factor and increased endothelial growth factor and vascular endothelial growth factor expression compared to male donor MSCs [133]. Furthermore, in a mouse model of myocardial infarction, treatment with female MSCs produced greater improvement of cardiac functional endpoints than treatment with male MSCs [134]. Estradiol has been shown to contribute to these differences [135, 136]. A more complete understanding of how MSCs are influenced by donor sex and recipient hormonal environment is needed to address sex-related disparities in clinical outcomes as well as to optimize transplanted MSC function and survival.

Advertisement

3. MSCs as a regenerative therapeutic for cardiovascular diseases

The hypothesis that exogenously delivered stem cells would promote organ regeneration through transdifferentiation into tissue-specific cells sparked interest in stem cell research and cell-based therapy and was originally supported by studies in the heart [82] where MSCs become cardiomyocyte-like cells and endothelial cells [41, 43]. However, subsequent studies have revealed that the MSC-mediated cardiac regenerative process is more complex than was initially envisioned (Figure 6).

Figure 6.

Effects Of mesenchymal stem cell therapy in heart disease.

3.1. Clinical trials in cardiac disease

Multiple clinical trials suggest that MSCs can ameliorate left ventricular remodeling and improve cardiac function in patients with acute and chronic ischemic cardiomyopathy [7, 9, 11, 72, 84, 115, 116, 137, 138, 139, 140, 141]. The Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy (TAC-HFT) trial demonstrated reverse remodeling and improved regional contractility of the scar as well as improved functional capacity and quality of life over 1 year in patients with chronic ischemic cardiomyopathy treated with transendocardial injection of autologous bone marrow-derived MSCs versus bone marrow mononuclear cells or placebo [9, 142]. The mesenchymal stromal cells in chronic ischemic Heart Failure (MSC-HF) trial showed that intramyocardial injection of autologous bone marrow-derived MSCs in patients with severe ischemic cardiomyopathy improved ventricular function and myocardial mass [140]. The same group showed that intramyocardial delivery of autologous MSCs into patients with coronary heart disease and refractory angina provided a sustained effect (3-year follow-up) in improving exercise capacity and ventricular function, and reducing hospitalization rates and revascularizations [143]. As mentioned previously, the CHART-1 study also demonstrated the anti-remodeling properties of cardiopoietic MSCs at the 1-year follow-up [72]. Encouraging results from preclinical studies with combination therapy [28, 79] have led to the initiation of the CONCERT-HF (NCT02501811) trial by the Cardiovascular Cell Therapy Research Network (CCTRN) in an effort to examine the effects of the transendocardial delivery of a combination of autologous bone marrow-derived MSCs and cardiac progenitor cells into patients with ischemic cardiomyopathy.

Autologous adipose tissue-derived MSCs are also undergoing investigation in the cardiovascular field. The adipose-derived stromal cells for treatment of patients with chronic ischemic heart disease (MyStromalCell) trial was a phase II, first-in-man, single-center, double-blind, randomized, and placebo-controlled study of intramyocardial injections of autologous adipose-derived MSCs in patients with chronic ischemic heart disease and refractory angina but preserved ejection fraction [111, 112]. The MSCs were obtained from abdominal adipose tissue, culture-expanded in vitro and stimulated with vascular endothelial growth factor-A (VEGF-A) (165) the week before treatment. The six month follow-up results demonstrated safety, and although a significant increase in exercise capacity was observed in the patients treated with the MSCs but not with placebo, there was no statistically significant difference between the MSC and placebo treatment groups.

An important issue in this new field is whether MSCs can be used as an allograft [5, 7, 89], avoiding the need for bone marrow aspiration of patients and tissue culture delays prior to treatment. Furthermore, the function of autologous MSCs may be impaired in patients with comorbidities and/or advanced age [101, 102, 103, 104]. A meta-analysis of 82 preclinical studies [144] demonstrated that allogeneic therapy is safe and at least as effective as autologous MSC therapy, suggesting that allogeneic MSCs are characteristically immunomodulatory, as discussed above.

The therapeutic benefit of allogeneic MSCs versus placebo delivered intravenously has been investigated in patients after acute MI [11, 145, 146]. Not only did these results show the safety of allogeneic MSC delivery to humans, but also moreover, echocardiography demonstrated a 6% increase in ejection fraction at 3 months for patients treated with MSCs. Moreover, the percutaneous stem cell injection delivery effects on neo-myogenesis (POSEIDON) trial compared allogeneic vs. autologous MSCs delivered by transendocardial stem cell injection in patients with chronic ischemic cardiomyopathy and showed that both MSC types are safe and clinically effective [7, 147]. Similarly, the percutaneous stem cell injection delivery effects on neo-myogenesis – dilated cardiomyopathy (POSEIDON-DCM) trial demonstrated safety and efficacy of transendocardial autologous vs. allogeneic MSC therapy in patients with non-ischemic, dilated cardiomyopathy, with a cardiac function efficacy preference toward allogeneic MSCs [5].

The transendocardial stem cell injection delivery effects on neomyogenesis study (TRIDENT) trial compared the safety and efficacy of two doses (20 million and 100 million) of allogeneic bone marrow-derived human MSCs delivered transendocardially in patients with ischemic cardiomyopathy [116]. Although both cell doses reduced scar size, only the 100 million doses increased LVEF, highlighting the crucial role of cell dose in the responses to cell therapy. In phase 2 dose-escalation study investigating immunoselected (Stro-1/Stro-3+ enriched), allogeneic bone marrow-derived MPCs (25, 75, and 150 million cells) delivered transendocardially in patients with ischemic and non-ischemic heart failure, no differences were observed in LVEF at 12 months of follow-up, although the 150 million MPC group had a significant reduction in left ventricular end-systolic and end-diastolic volumes, a measure of reverse remodeling, at 6 months and a non-significant decrease of both ventricular volumes at 12 months [56]. These and other ongoing studies determining the optimal dose and delivery are essential to advance the field, decipher mechanism(s) of action, and enhance planning of pivotal Phase III trials [148, 149, 150, 151, 152].

A recent trial assessed the safety and preliminary efficacy of intravenously administered, allogeneic, ischemia-tolerant MSCs in patients with non-ischemic cardiomyopathy [153]. Ischemia-tolerant MSCs are grown under chronic hypoxic conditions and have been shown to better migrate toward wound healing-related cytokines and cytokines found in ischemic tissues and express higher levels of hypoxia-inducible factor-1 [154]. These studies suggested that ischemia-tolerant MSCs may be therapeutically more effective than MSCs grown under normoxic conditions. An increase in LVEF and reductions in end-systolic and end-diastolic volumes were observed at three months of follow up in the treated group but was not significantly different from the placebo group. Functional capacity and health status were significantly improved in the MSC treated group compared to placebo.

MSCs derived from umbilical cord (UC-MSCs) have also been tested in patients with heart failure. The randomized clinical trial of intravenous infusion umbilical cord mesenchymal stem cells on cardiopathy (RIMECARD) trial is a randomized, double-blind, placebo-controlled trial that evaluated the safety and efficacy of UC-MSCs administered intravenously in patients with heart failure of ischemic or non-ischemic origin [141]. Infusion of allogeneic UC-MSCs was safe, with no development of alloantigen directed antibodies post-infusion, and effective in improving LVEF, functional status, and quality of life. Intramyocardial delivery of UC-MSCs in patients with heart failure has also been shown to produce improvements in LVEF and end-systolic volume in patients with severe heart failure [155].

Ongoing clinical trials are assessing the safety and efficacy of allogeneic MSC therapy in patients with acute myocardial infarction, chronic ischemic and non-ischemic cardiomyopathy, and left ventricular assist devices. These studies will continue to pave the way for the development of allogeneic cell-based regenerative therapies for structural and functional disorders of the myocardium. The results from cardiovascular stem cell clinical trials are so far promising, with recent trials highlighting the vast therapeutic potential of allogeneic over autologous stem cells. However, many challenges remain, such as addressing long-term safety, serial stem cell injections, and optimal cell type, dose, and delivery route [148, 149, 150, 151, 152].

3.2. Vascular disease

Endothelial dysfunction is characterized by impaired endothelial vasodilation, a proinflammatory and prothrombotic state, and impaired bioactivity of EPCs and contributes to the pathophysiology of most forms of cardiovascular disease, including hypertension, coronary artery disease, heart failure, peripheral vascular disease, kidney disease, diabetes mellitus, and metabolic syndrome [156, 157]. Endothelial function is implicated in heart failure [158] and we have studied the therapeutic potential of MSCs in restoring endothelial function in patients with ischemic and non-ischemic cardiomyopathy [81]. As mentioned above, individuals with heart failure received either autologous or allogeneic MSCs, and those in the allogeneic MSC group exhibit increased EPC colony formation and improved flow-mediated vasodilation (FMD), both of which strongly correlate with improved endothelial function [158, 159] (Figure 7). Moreover, patients who received allogeneic MSCs had reduced levels of VEGF. Elevated VEGF is associated with heart failure progression [160]. The concordant restitution of these parameters to near normal after allogeneic MSC therapy has significant clinical implications for the heart failure population and may play a critical role in the advancement of cardiovascular treatment modalities.

Figure 7.

MSCs in vascular disease. Allogeneic mesenchymal stem cell therapy can help restore endothelial function in patients with cardiomyopathy by increasing EPC CFUs (A) and improving FMD (E) when compared to autologous therapy (B and F). Representative EPC-CFUs plated on fibronectin for 5 days before (C) and after (D) allogeneic MSC administration (magnification 20x).Reproduced from Premer C et al., EBioMed, 2015.

It is well established that cardiovascular disease is the leading cause of death and disability among people with type 2 diabetes mellitus [161] and has long been appreciated that endothelial dysfunction underlies the high rates of cardiovascular disease associated with long-term diabetes [162]. The persistent hyperglycemia and other metabolic abnormalities directly affect the endothelium, contributing to the pathophysiology of disease [163]. Based on our findings of improved endothelial function after allogeneic MSC treatment in patients with heart failure [81], we are conducting a clinical trial entitled, Allogeneic Mesenchymal Human Stem Cells Infusion Therapy for Endothelial Dysfunction in Diabetic Subjects (ACESO; NCT02886884) to investigate whether intravenously delivered MSCs restore endothelial function parameters, including FMD and EPC function, as well as decrease circulating inflammatory markers and improve clinical parameters of diabetes. Similarly, the Intravenous Infusion of Umbilical Cord Tissue (UC) Derived Mesenchymal Stem Cells (MSCs) Versus Bone Marrow (BM) Derived MSCs to Evaluate Cytokine Suppression in Patients With Chronic Inflammation Due to Metabolic Syndrome (CERES; NCT03059355) trial is testing MSC therapies to restore endothelial function.

Peripheral artery disease is generally caused by atherosclerosis in which cholesterol plaque builds up, ultimately weakening blood vessel walls and restricting blood flow, severely impairing endothelial function. The evaluation of cell therapy on exercise performance and limb perfusion in peripheral artery disease: The CCTRN patients with intermittent claudication injected with ALDH bright cells (PACE) Trial demonstrated safety but no improvement in peak walking time or capillary perfusion [164]. In patients with complete occlusion of femoral arteries, a post-hoc exploratory analysis suggested an improvement in the number of collateral arteries. Future clinical trials testing different cell types, doses, and administration routes are needed to optimize peripheral artery disease treatment.

Advertisement

4. MSCs as immunomodulatory, anti-Inflammatory, anti-fibrotic, and anti-rejection therapy

MSCs exhibit immune-privileged properties in vitro and in vivo [165] likely due to the absence of MHC II, B-7 costimulatory molecule, and CD40 ligand [90, 91, 92, 166] (Figure 8). The lack of costimulatory molecules prevents T-cell responses and also induces an immunosuppressive local microenvironment through the production of prostaglandins and other soluble mediators including nitric oxide, indoleamine 2,3-dioxygenase, and heme oxygenase-1 [92, 167, 168, 169, 170]. MSCs reduce the respiratory burst that follows neutrophilic responses by releasing interleukin (IL)-6 [171]. They also inhibit the differentiation of immature monocytes into dendritic cells hence the antigen presentation to naïve T cells is greatly impaired [172]. In addition, MSCs release soluble factors, such as hepatocyte growth factor and transforming growth factor (TGF)-β1 [173], that suppress the proliferation of cytotoxic and helper T-(Th) cells. MSCs also stimulate Foxp3+ regulatory T cells with concurrent suppression of Th1, Th2, or Th17 responses [174]. These findings suggest that MSCs are an effective therapeutic strategy to induce tolerance in solid organ transplantation [175].

Figure 8.

Immunomodulatory effects of mesenchymal stem cells. MSCs are immunoprivileged cells that inhibit both innate (neutrophils, dendritic cells, and natural killer cells) and adaptive (T cells and B cells) immune cells.

4.1. Transplantation

Le Blanc et al.first reported the clinical immunoregulatory response to MSCs in a case of severe, treatment-resistant grade IV acute graft-vs-host disease (GVHD) [13]. A multicenter phase 2 trials for steroid-resistant, severe acute GVHD confirmed this observation [12] and MSCs obtained from HLA-identical siblings, haploidentical third-party donors, or HLA-mismatched third-party donors were similarly effective. Recently, infusion of MSCs the day of hematopoietic cell transplantation (HCT) promotes engraftment and improves outcomes. A pilot study of allogeneic MSC infusion before nonmyeloablative HCT from HLA-mismatched donors showed sustained engraftment in 19 out of 20 patients, and the 1 year incidence of nonrelapse mortality, relapse, overall survival, progression-free survival, and death from GVHD was favorable compared to a historic control group [176]. In another pilot study evaluated the effect of infusion of MSCs at the time of dual transplant of cord blood and third-party donor mobilized hematopoietic stem cells regarding tolerance, cord blood engraftment, and effects on acute GVHD, both preventive and therapeutic [177]. MSC infusions were effective for treating severe acute GVHD, but no significant differences in cord blood engraftment and incidence of severe acute GVHD were observed. Although there is accumulating evidence of safety from these small pilot studies [96], randomized trials are necessary to establish efficacy.

A single-site, open-label, randomized controlled clinical trial in 159 patients undergoing living-related donor kidney transplantation showed that induction therapy with autologous MSCs resulted in lower incidence of acute rejection, decreased the risk of opportunistic infection, and better estimated renal graft function at 6 months compared with anti-IL-2 receptor antibody induction therapy [16]. However, graft function and rejection rates were similar after 1 year [178]. Therefore, MSC therapy can safely replace induction immunotherapy, reducing opportunistic infections, without compromising graft function and survival [179].

Despite these encouraging results, the long-term safety of MSC transplants needs to be further investigated in chronically immunosuppressed patients that are at increased risk for opportunistic infections and tumors [132, 180]. In this regard, a clinical trial evaluated the safety and tolerability of third party MSC administration after liver transplantation. Patients enrolled in the experimental arm were infused with a single dose of 1.5 million MSCs/kg, 3(±2) days after the liver transplantation [181]. There was no impairment in liver transplant function and no increased rate of opportunistic infection or new cancer detected following MSC infusion. In addition, there was no difference in overall rates of rejection or graft survival. Weaning of immunosuppression in MSC recipients was not successful.

Issues needing further investigation include dose, timing and site of administration, interaction with immunosuppressive drugs, and whether MSCs are effective at preventing acute rejection and/or inducing tolerance. In a murine kidney transplant model, it was shown that MSC administration before (day -1) but not a few days after kidney transplantation avoided the acute deterioration of graft function while maintaining the immunomodulatory effect of MSCs [182]. Moreover, a clinical study found that autologous bone marrow-derived MSC infusion at day 7 post-kidney transplant induced acute kidney graft dysfunction, attributed to engraftment syndrome [183], although MSC infusion was associated with lower memory/effector CD8+ T cells, expansion of CD4+ regulatory T cells, and reduction of donor-specific CD8+ T-cell cytotoxicity compared with control kidney transplant recipients given the same induction therapy (basiliximab/low dose thymoglobulin) but not MSCs [184].

Islet cell transplantation combined with MSC therapy for type 1 diabetes in a cynomolgus monkey model provides clinical evidence for the anti-rejection effect of MSCs [185]. MSC treatment significantly enhanced islet engraftment and functions one month post-transplant, compared with animals receiving islets without MSCs. In addition, infusions of donor or third-party MSCs resulted in a reversal of rejection episodes and prolongation of islet function. Stable islet allograft function was associated with increased numbers of regulatory T cells in peripheral blood, suggesting that MSCs enhance islet engraftment, thereby decreasing the numbers of islets needed to achieve insulin independence.

4.2. Autoimmune diseases

Autologous MSC transplantation evaluated in clinical trials of amyotrophic lateral sclerosis [18] and multiple sclerosis [17, 186] is safe and associated with increased proportion of CD4+ CD25+ regulatory T cells, decreased proliferative responses of lymphocytes, and lower expression of co-stimulatory molecules (CD40+, CD83+, and CD86+), and HLA-DR on myeloid dendritic cells within 24 hours of transplantation [17]. In a randomized, placebo-controlled, phase 2 trial of multiple sclerosis, bone marrow-derived MSCs were also found to reduce inflammatory MRI parameters, supporting their anti-inflammatory and immunomodulatory properties [187]. Moreover, autologous and allogeneic MSC therapy showed evidence of benefit in other autoimmune disorders such as refractory Crohn’s disease [188, 189, 190, 191] and systemic lupus erythematosus [14, 192, 193], respectively. Although there are no clinical trial results in patients with rheumatoid arthritis (clinical trials are ongoing; NCT01851070), in vitro studies show that allogeneic MSCs or MSC-differentiated chondrocytes inhibit the proliferation and activation of collagen type II-stimulated T-cells and the secretion of proinflammatory cytokines, including IFN-gamma and TNF-alpha by CD4+ and CD8+ T cells, while increasing the secretion of IL-10 and restoring the secretion of IL-4 [194, 195]. These results suggest that the immunomodulatory and anti-inflammatory effects of MSCs offers an effective therapeutic modality for arthritic diseases [195], and several clinical trials are ongoing evaluating bone marrow, adipose, and UC-derived MSCs.

Transplanted MSCs exert a protective effect in type 1 diabetes mellitus [196]. MSCs localize to the pancreas after intravenous transplantation and lower blood sugar levels [197], similar to MSCs isolated from the Wharton’s jelly of the umbilical cord, which differentiated into mature islet-like cell clusters and possessed insulin-producing ability in vitro and in vivo [198]. Transplanted MSCs lower blood sugar through secretion of trophic cytokines that promote endogenous pancreatic stem cells in the ductal epithelium to differentiate into new ß-cells and directly differentiate into functionally competent, new ß-cells [199]. Furthermore, MSCs produce a variety of cytokines and growth factors, which could promote survival of surrounding cells and improve the microenvironment of pancreas [200]. Based on these findings, clinical trials have been initiated to test safety and therapeutic efficacy. A pilot, randomized, controlled, and open-label trial investigated the potential benefits on metabolic control and safety of combined umbilical cord-derived MSCs and autologous bone marrow mononuclear cell transplantation without immunotherapy in patients with established type 1 diabetes [201]. The treatment was not only well tolerated, but at 1 year, metabolic measures, including hemoglobin A1C, fasting glycemia, and daily insulin requirements, improved in the treated patients, whereas it decreased in control subjects. In another clinical study, treatment with a single intravenous infusion of autologous MSCs was tested in new-onset type 1 diabetic patients and found to be safe and to show benefit in slowing disease progression and preserving β-cell function [202].

4.3. Pulmonary diseases

A recent randomized, double-blinded, placebo-controlled study demonstrated the safety of systemic administration of allogeneic MSCs in patients with moderate to severe chronic obstructive pulmonary disease (COPD) [15], however, there were no differences in the frequency of COPD exacerbations, pulmonary function tests, or quality of life after 2 years of follow up. A significant decrease in levels of circulating C-reactive protein (CRP) was observed in MSC-treated patients who had elevated CRP levels at study entry, suggesting a beneficial effect of MSC infusion on systemic inflammation [15].

Idiopathic Pulmonary Fibrosis (IPF) is a lung disease characterized by progressive interstitial fibrosis leading to hypoxemic respiratory failure for which no effective treatment exists [203]. Histologically, there is evidence of alveolar epithelial cell injury, interstitial inflammation, fibroblast proliferation, and extracellular matrix collagen deposition. Because MSCs home to sites of injury, inhibit inflammation and contribute to epithelial tissue repair, they offer a potential therapy for IPF [203]. The phase 1 clinical trial entitled allogeneic human mesenchymal stem cells in patients with IPF via intravenous delivery (AETHER) demonstrated the safety of bone marrow-derived MSCs in nine patients with mild to moderate IPF [10]. A 3.0% mean decline in percent predicted forced vital capacity, and 5.4% mean decline in percent predicted diffusing capacity of the lungs for carbon monoxide was observed by 60 weeks post-MSC infusion, suggesting potential for efficacy.

Of note, a study has provided evidence of a resident c-kit+ multi-potent stem cell in the human lung [204]. These lung c-kit+ stem cells were shown to have the capacity to develop into bronchioles, alveoli, and pulmonary vessels, supporting the notion that they play an important role in lung homeostasis and tissue regeneration after injury. Although the therapeutic implications of these findings have not been investigated, we can infer from findings in ischemic heart disease models that there is the potential for MSCs to stimulate endogenous c-kit+ lung stem cell proliferation and differentiation, thereby facilitating lung tissue repair and regeneration.

4.4. Cutaneous wounds

Chronic, non-healing cutaneous wounds are a major cause of morbidity. The ability of MSCs to differentiate into various cell types and their capacity to secrete factors important in accelerating wound healing have made cell therapy a promising strategy for tissue repair and regeneration [24, 205]. Although both autologous and allogeneic MSCs appear to be well suited as wound healing therapies, allogeneic MSCs derived from young healthy donors may have an advantage over autologous sources where age and systemic comorbidities, such as diabetes, chronic renal failure, and arterial or venous insufficiency, are a contributing factor. The effects of aging and systemic illness on MSCs include impaired cell migration, reduced growth factor production, and poor tissue remodeling [24]. A study evaluated MSCs and fibroblasts derived from normal donors and chronic wound patients to characterize the induction of mobilization when these cells are mixed as well as examine the effect of soluble factors on fibroblast migration [206]. These studies showed that MSCs participate in skin wound closure by affecting dermal fibroblast migration in a dose-dependent manner, but impairments were noted in chronic wound patient fibroblasts and MSCs as compared with those derived from normal donors. These results support the notion that allogeneic MSCs from “healthy” donors provide greater efficacy for wound healing compared to autologous MSCs. Such promising findings have supported the use of MSCs in animal models of burn wound healing [207, 208, 209]. Consequently, a clinical trial entitled “Stem Cell Therapy to Improve Burn Wound Healing” (NCT02104713) is currently underway and is examining the efficacy of allogeneic MSCs in burn wound closure for patients with a 2nd degree burn wounds of less than 20% total body surface area.

4.5. Neurological diseases

MSCs are also considered a promising therapeutic strategy for acute injury and progressive degenerative diseases of the central nervous system [210], such as spinal cord injury [211, 212]ischemic stroke [21, 22, 213, 214] Parkinson’s disease [215, 216] traumatic brain injury [217, 218]multiple sclerosis [17, 186, 219, 220] and multiple system atrophy [23]. Studies suggest that the neuroprotective effect of MSCs is mediated by the production of various trophic factors, including brain-derived neurotrophic factors, nerve growth factor, and insulin-like growth factor-1, which contribute to recovering neurobehavioral function and stimulating endogenous regeneration [210, 212, 221]. In addition, MSCs home to injured brain tissues and exert immunoregulatory properties, reduce apoptosis, and improve neuronal cell survival [215, 217, 221]. However, it is unclear if MSCs differentiate into neural cells in vivo [210, 212].

4.6. Liver diseases

The anti-fibrotic properties of MSCs may exert therapeutic effects in liver regeneration and disease. MSCs inhibit activated fibrogenic cells such as hepatic stellate cells [222]. Numerous preclinical studies on bone marrow [223, 224, 225]. adipose tissue [226], and UC-derived [227]MSC treatment for improvement of liver fibrosis have been conducted and have reported reductions in liver fibrosis as well as improvements in hepatic function. Indeed, MSC based therapies for patients with end-stage liver disease, have shown promise in phaseIand II clinical trials [19, 20, 228]. MSC transplantation was safe and well-tolerated and hepatic function improved in patients with liver fibrosis [20]. Moreover, the biochemical hepatic index and model for end-stage liver disease (MELD) score were markedly improved from 2 to 3 weeks post transplantation [19]. However, the long-term hepatic function was not significantly enhanced in patients with liver failure caused by hepatitis B [19]. Notably, many of these clinical trials differ in MSC source, and liver pathology [229, 230, 231, 232] and perhaps certain type of MSCs may serve as better therapeutic options for specific liver pathologies. These early stage studies and more recent clinical trials suggest that MSC transplantation is safe and may confer benefit to patients with liver cirrhosis and various kinds of liver diseases [233].

4.7. Aging frailty

Frailty is a medical syndrome that increases in prevalence with age and augments the risk for adverse health outcomes, including mortality, hospitalization, fall, and institutionalization. Markers of frailty include age-associated declines in lean body mass, strength, endurance, balance, walking performance, and activity; and are accompanied by declines in physiologic reserve in most organ systems. Together, these symptoms lead to the loss of homeostasis and the capability to withstand stressors and resulting vulnerabilities. Notably, there is a robust correlation between frailty and biomarkers of inflammation. There is also evidence that endogenous stem cell production decreases with age, likely contributing to reduce ability to regenerate and repair organs and tissues. Therefore, a regenerative treatment strategy could ameliorate signs and symptoms of aging frailty. Currently, there are no approved treatments for frail patients and therefore no established standard of care. There are specific features of the frailty syndrome that support the hypothesis that MSCs will also ameliorate or improve frailty. Indeed, in a pilot study and subsequently in a randomized, double-blind, dose-finding study, we demonstrated safety of intravenous infusion of allogeneic MSCs into elderly, frail individuals and found significant improvements in physical performance measures and inflammatory biomarkers [6, 234, 235]. These findings suggest that frailty can ultimately be prevented or attenuated, and the link between frailty and inflammation offers a potential therapeutic target, addressable by cell therapy

Advertisement

5. Conclusions

The promising cell-based therapy field has exploded in the past decade and currently, MSCs from various sources, mainly bone marrow and adipose-derived, are being evaluated in phase I and II trials for a myriad of chronic, disabling disorders with no currently effective therapies. Although preclinical studies provide mechanistic insights into therapeutic effects of MSCs and phase I/II studies provide evidence of safety in the short-term, questions regarding most effective dose, route of administration, interaction with other concurrent therapies, sustainability/durability of effect, and adverse effects, including opportunistic infections and tumor development or progression, remain to be resolved. Addressing these questions will require rigorously conducted, multicenter clinical trials with well-defined clinical outcomes, longer duration of follow up, and more patients [151, 236].

Advertisement

Funding

JMH and IHS are supported by the National Institute of Health (NIH) grants, UM1 HL113460, 1R01 HL134558-01, 1R01 HL137355-01, as well as by the Starr and Soffer Family Foundations.

Advertisement

Disclosures

JMH reported having a patent for cardiac cell-based therapy. He holds equity in Vestion Inc. and maintains a professional relationship with Vestion Inc. as a consultant and member of the Board of Directors and Scientific Advisory Board. JMH is the Chief Scientific Officer, a compensated consultant and advisory board member for Longeveron, and holds equity in Longeveron. JMH is also the co-inventor of intellectual property licensed to Longeveron. Longeveron LLC and Vestion Inc. did not participate in funding this work. The other authorreports no conflicts.

References

  1. 1. Hatzistergos KE, Quevedo H, Oskouei BN, et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circulation Research. 2010 Oct 1;107(7):913-922. DOI: 10.1161/CIRCRESAHA.110.222703
  2. 2. Cagliani J, Grande D, Molmenti EP, et al. Immunomodulation by Mesenchymal Stromal Cells and Their Clinical Applications. Journal of Stem Cell and Regenerative Biology. 2017;3(2). DOI: 10.15436/2471-0598.17.022
  3. 3. Tompkins BA, Balkan W, Winkler J, et al. Preclinical Studies of Stem Cell Therapy for Heart Disease. Circulation Research. 2018 Mar 30;122(7):1006-1020. DOI: 10.1161/CIRCRESAHA.117.312486
  4. 4. Lalu MM, McIntyre L, Pugliese C, et al. Safety of Cell Therapy with Mesenchymal Stromal Cells (SafeCell): A Systematic Review and Meta-Analysis of Clinical Trials. PLoS One. 2012;7(10):e47559. DOI: 10.1371/journal.pone.0047559
  5. 5. Hare JM, DiFede DL, Rieger AC, et al. Randomized Comparison of Allogeneic Versus Autologous Mesenchymal Stem Cells for Nonischemic Dilated Cardiomyopathy: POSEIDON-DCM Trial. Journal of the American College of Cardiology. 2017 Feb 07;69(5):526-537. DOI: 10.1016/j.jacc.2016.11.009
  6. 6. Tompkins BA, DiFede DL, Khan A, et al. Allogeneic Mesenchymal Stem Cells Ameliorate Aging Frailty: A Phase II Randomized, Double-Blind, Placebo-Controlled Clinical Trial. The journals of gerontology Series A, Biological sciences and medical sciences. 2017 Oct 12;72(11):1513-1522. DOI: 10.1093/gerona/glx137
  7. 7. Hare JM, Fishman JE, Gerstenblith G, et al. Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. Journal of the American Medical Association. 2012 Dec 12;308(22):2369-2379. DOI: 10.1001/jama.2012.25321
  8. 8. von Bahr L, Batsis I, Moll G, et al. Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation. Stem Cells 2012 Jul;30(7):1575-1578. DOI: 10.1002/stem.1118
  9. 9. Heldman AW, DiFede DL, Fishman JE, et al. Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial. Journal of the American Medical Association. 2014 Jan;311(1):62-73. DOI: 10.1001/jama.2013.282909
  10. 10. Glassberg MK, Minkiewicz J, Toonkel RL, et al. Allogeneic Human Mesenchymal Stem Cells in Patients With Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER): A Phase I Safety Clinical Trial. Chest. 2017 May;151(5):971-981. DOI: 10.1016/j.chest.2016.10.061
  11. 11. Hare JM, Traverse JH, Henry TD, et al. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. Journal of the American College of Cardiology 2009 Dec 8;54(24):2277-86. DOI: 10.1016/j.jacc.2009.06.055
  12. 12. Le Blanc K, Frassoni F, Ball L, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 2008 May 10;371(9624):1579-86. DOI: 10.1016/S0140-6736(08)60690-X
  13. 13. Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004 May 1;363(9419):1439-41. DOI: 10.1016/S0140-6736(04)16104-7
  14. 14. Liang J, Zhang H, Hua B, et al. Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study. Annals of the Rheumatic Diseases 2010 Aug;69(8):1423-9. DOI: 10.1136/ard.2009.123463
  15. 15. Weiss DJ, Casaburi R, Flannery R, et al. A Placebo-Controlled Randomized Trial of Mesenchymal Stem Cells in Chronic Obstructive Pulmonary Disease. Chest 2012 Nov 22. DOI: 10.1378/chest.12-2094
  16. 16. Tan J, Wu W, Xu X, et al. Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA: The Journal of the American Medical Association 2012 Mar 21;307(11):1169-77. DOI: 10.1001/jama.2012.316
  17. 17. Karussis D, Karageorgiou C, Vaknin-Dembinsky A, et al. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Archives of Neurology 2010 Oct;67(10):1187-94. DOI: 10.1001/archneurol.2010.248
  18. 18. Mazzini L, Ferrero I, Luparello V, et al. Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis: A Phase I clinical trial. Experimental Neurology 2010 May;223(1):229-37. DOI: 10.1016/j.expneurol.2009.08.007
  19. 19. Peng L, Xie DY, Lin BL, et al. Autologous bone marrow mesenchymal stem cell transplantation in liver failure patients caused by hepatitis B: short-term and long-term outcomes. Hepatology 2011 Sep 2;54(3):820-8. DOI: 10.1002/hep.24434
  20. 20. Kharaziha P, Hellstrom PM, Noorinayer B, et al. Improvement of liver function in liver cirrhosis patients after autologous mesenchymal stem cell injection: a phase I-II clinical trial. European Journal of Gastroenterology & Hepatology 2009 Oct;21(10):1199-205. DOI: 10.1097/MEG.0b013e32832a1f6c
  21. 21. Honmou O, Houkin K, Matsunaga T, et al. Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. Brain: A Journal of Neurology. 2011 Jun;134(Pt 6):1790-807. DOI: 10.1093/brain/awr063
  22. 22. Lee JS, Hong JM, Moon GJ, et al. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells. 2010 Jun;28(6):1099-1106. DOI: 10.1002/stem.430
  23. 23. Lee PH, Lee JE, Kim HS, et al. A randomized trial of mesenchymal stem cells in multiple system atrophy. Annals of Neurology. 2012 Jul;72(1):32-40. DOI: 10.1002/ana.23612
  24. 24. Badiavas AR, Badiavas EV. Potential benefits of allogeneic bone marrow mesenchymal stem cells for wound healing. Expert Opinion on Biological Therapy. 2011 Nov;11(11):1447-1454. DOI: 10.1517/14712598.2011.606212
  25. 25. Golpanian S, Wolf A, Hatzistergos KE, et al. Rebuilding the Damaged Heart: Mesenchymal Stem Cells, Cell-Based Therapy, and Engineered Heart Tissue. Physiological Reviews. 2016 Jul;96(3):1127-1168. DOI: 10.1152/physrev.00019.2015
  26. 26. White IA, Sanina C, Balkan W, et al. Mesenchymal Stem Cells in Cardiology. Methods in Molecular Biology. 2016;1416:55-87. DOI: 10.1007/978-1-4939-3584-0_4
  27. 27. Shin TH, Kim HS, Choi SW, et al. Mesenchymal Stem Cell Therapy for Inflammatory Skin Diseases: Clinical Potential and Mode of Action. International Journal of Molecular Sciences. 2017 Jan 25;18(2). DOI: 10.3390/ijms18020244
  28. 28. Williams AR, Hatzistergos KE, Addicott B, et al. Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction. Circulation. 2013;127(2):213-23. DOI: 10.1161/circulationaha.112.131110
  29. 29. Natsumeda M, Florea V, Rieger AC, et al. A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration. Journal of the American College of Cardiology. 2017 Nov 14;70(20):2504-2515. DOI: 10.1016/j.jacc.2017.09.036
  30. 30. Hatzistergos KE, Saur D, Seidler B, et al. Stimulatory effects of mesenchymal stem cells on Ckit+ cardiac stem cells are mediated by Sdf1/Cxcr4 And Scf/Ckit signaling pathways. Circulation Research. 2016 Sep 30;119(8):921-930. DOI: 10.1161/CIRCRESAHA.116.309281
  31. 31. Luria EA, Panasyuk AF, Friedenstein AY. Fibroblast colony formation from monolayer cultures of blood cells. Transfusion. 1971 Nov-Dec;11(6):345-349
  32. 32. Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell and Tissue Kinetics. 1970 Oct;3(4):393-403
  33. 33. Williams AR, Hare JM. Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circulation Research. 2011 Sep 30;109(8):923-940. DOI: 10.1161/CIRCRESAHA.111.243147
  34. 34. Pittenger MF, Mosca JD, McIntosh KR. Human mesenchymal stem cells: progenitor cells for cartilage, bone, fat and stroma. Current Topics in Microbiology and Immunology. 2000;251:3-11
  35. 35. Zuk PA, Zhu M, Mizuno H, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Engineering. 2001 Apr;7(2):211-228. DOI: 10.1089/107632701300062859
  36. 36. da Silva ML, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. Journal of Cell Science. 2006 Jun 1;119(Pt 11):2204-2213 DOI: jcs.02932 [pii] 10.1242/jcs.02932
  37. 37. Chong JJ, Chandrakanthan V, Xaymardan M, et al. Adult cardiac-resident MSC-like stem cells with a proepicardial origin. Cell Stem Cell. 2011 Dec 2;9(6):527-540. DOI: 10.1016/j.stem.2011.10.002
  38. 38. Cao Y, Gomes SA, Rangel EB, et al. S-nitrosoglutathione reductase-dependent PPAR-gamma denitrosylation participates in MSC-derived adipogenesis and osteogenesis. The Journal of Clinical Investigation. 2015 Apr;125(4):1679-1691. DOI: 10.1172/JCI73780
  39. 39. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999 Apr 2;284(5411):143-147
  40. 40. Quevedo HC, Hatzistergos KE, Oskouei BN, et al. Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity. Proceedings of the National Academy of Sciences of the United States of America. 2009 Aug 18;106(33):14022-14027. DOI: 10.1073/pnas.0903201106
  41. 41. Oswald J, Boxberger S, Jorgensen B, et al. Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells. 2004;22(3):377-384. DOI: 10.1634/stemcells.22-3-377
  42. 42. Liechty KW, MacKenzie TC, Shaaban AF, et al. Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep. Nature Medicine. 2000;6(11):1282-1286
  43. 43. Makino S, Fukuda K, Miyoshi S, et al. Cardiomyocytes can be generated from marrow stromal cells in vitro. The Journal of Clinical Investigation. 1999 Mar;103(5):697-705. DOI: 10.1172/JCI5298
  44. 44. Szaraz P, Gratch YS, Iqbal F, et al. In Vitro Differentiation of Human Mesenchymal Stem Cells into Functional Cardiomyocyte-like Cells. Journal of visualized experiments: JoVE. 2017 Aug 9;126. DOI: 10.3791/55757
  45. 45. Bhuvanalakshmi G, Arfuso F, Kumar AP, et al. Epigenetic reprogramming converts human Wharton's jelly mesenchymal stem cells into functional cardiomyocytes by differential regulation of Wnt mediators. Stem Cell Research & Therapy. 2017 Aug 14;8(1):185. DOI: 10.1186/s13287-017-0638-7
  46. 46. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-317. DOI: 10.1080/14653240600855905
  47. 47. Jones EA, Kinsey SE, English A, et al. Isolation and characterization of bone marrow multipotential mesenchymal progenitor cells. Arthritis and Rheumatism. 2002 Dec;46(12):3349-3360. DOI: 10.1002/art.10696
  48. 48. Porada CD, Almeida-Porada G. Mesenchymal stem cells as therapeutics and vehicles for gene and drug delivery. Advanced Drug Delivery Reviews. 2010 Sep 30;62(12):1156-1166. DOI: 10.1016/j.addr.2010.08.010
  49. 49. Hoogduijn MJ, Betjes MG, Baan CC. Mesenchymal stromal cells for organ transplantation: different sources and unique characteristics? Current Opinion in Organ Transplantation. 2014 Feb;19(1):41-46. DOI: 10.1097/MOT.0000000000000036
  50. 50. Kern S, Eichler H, Stoeve J, et al. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells. 2006 May;24(5):1294-1301.DOI: 10.1634/stemcells.2005-0342
  51. 51. Psaltis PJ, Paton S, See F, et al. Enrichment for STRO-1 expression enhances the cardiovascular paracrine activity of human bone marrow-derived mesenchymal cell populations. Journal of Cellular Physiology. 2010 May;223(2):530-540. DOI: 10.1002/jcp.22081
  52. 52. Noort WA, Oerlemans MI, Rozemuller H, et al. Human versus porcine mesenchymal stromal cells: phenotype, differentiation potential, immunomodulation and cardiac improvement after transplantation. Journal of Cellular and Molecular Medicine. 2012 Aug;16(8):1827-1839. DOI: 10.1111/j.1582-4934.2011.01455.x
  53. 53. Psaltis PJ, Carbone A, Nelson AJ, et al. Reparative effects of allogeneic mesenchymal precursor cells delivered transendocardially in experimental nonischemic cardiomyopathy. JACC. Cardiovascular Interventions. 2010 Sep;3(9):974-983. DOI: 10.1016/j.jcin.2010.05.016
  54. 54. Gronthos S, Zannettino AC, Hay SJ, et al. Molecular and cellular characterisation of highly purified stromal stem cells derived from human bone marrow. Journal of Cell Science. 2003 May 1;116(9):1827-1835
  55. 55. Gronthos S, Fitter S, Diamond P, et al. A novel monoclonal antibody (STRO-3) identifies an isoform of tissue nonspecific alkaline phosphatase expressed by multipotent bone marrow stromal stem cells. Stem Cells and Development. 2007 Dec;16(6):953-963. DOI: 10.1089/scd.2007.0069
  56. 56. Perin EC, Borow KM, Silva GV, et al. A Phase II Dose-Escalation Study of Allogeneic Mesenchymal Precursor Cells in Patients With Ischemic or Nonischemic Heart Failure. Circulation Research. 2015 Aug 28;117(6):576-584. DOI: 10.1161/CIRCRESAHA.115.306332
  57. 57. Houtgraaf JH, de Jong R, Kazemi K, et al. Intracoronary infusion of allogeneic mesenchymal precursor cells directly after experimental acute myocardial infarction reduces infarct size, abrogates adverse remodeling, and improves cardiac function. Circulation Research 2013 Jul 5;113(2):153-166. DOI: 10.1161/CIRCRESAHA.112.300730
  58. 58. Mackay AM, Beck SC, Murphy JM, et al. Chondrogenic differentiation of cultured human mesenchymal stem cells from marrow. Tissue Engineering. 1998 Winter;4(4):415-428. DOI: 10.1089/ten.1998.4.415
  59. 59. Ng F, Boucher S, Koh S, et al. PDGF, TGF-beta, and FGF signaling is important for differentiation and growth of mesenchymal stem cells (MSCs): transcriptional profiling can identify markers and signaling pathways important in differentiation of MSCs into adipogenic, chondrogenic, and osteogenic lineages. Blood. 2008 Jul 15;112(2):295-307. DOI: 10.1182/blood-2007-07-103697
  60. 60. Caplan AI. Mesenchymal stem cells. Journal of Orthopaedic Research. 1991 Sep;9(5):641-650. DOI: 10.1002/jor.1100090504
  61. 61. Jaiswal N, Haynesworth SE, Caplan AI, et al. Osteogenic differentiation of purified, culture-expanded human mesenchymal stem cells in vitro. Journal of Cellular Biochemistry. 1997 Feb;64(2):295-312
  62. 62. Bruder SP, Jaiswal N, Haynesworth SE. Growth kinetics, self-renewal, and the osteogenic potential of purified human mesenchymal stem cells during extensive subcultivation and following cryopreservation. Journal of Cellular Biochemistry. 1997 Feb;64(2):278-294
  63. 63. Pereira RF, Halford KW, O'Hara MD, et al. Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage, and lung in irradiated mice. Proceedings of the National Academy of Sciences of the United States of America. 1995 May 23;92(11):4857-4861
  64. 64. Bruder SP, Fink DJ, Caplan AI. Mesenchymal stem cells in bone development, bone repair, and skeletal regeneration therapy. Journal of Cellular Biochemistry. 1994 Nov;56(3):283-294. DOI: 10.1002/jcb.240560303
  65. 65. Dennis JE, Merriam A, Awadallah A, et al. A quadripotential mesenchymal progenitor cell isolated from the marrow of an adult mouse. Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research. 1999 May;14(5):700-709. DOI: 10.1359/jbmr.1999.14.5.700
  66. 66. Schoolmeesters A, Eklund T, Leake D, et al. Functional profiling reveals critical role for miRNA in differentiation of human mesenchymal stem cells. PLoS One. 2009;4(5):e5605. DOI: 10.1371/journal.pone.0005605
  67. 67. Hatzistergos KE, Quevedo H, Oskouei BN, et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circulation Research. 2010 Oct 1;107(7):913-922. DOI: 10.1161/CIRCRESAHA.110.222703
  68. 68. Eschenhagen T, Bolli R, Braun T, et al. Cardiomyocyte Regeneration: A Consensus Statement. Circulation. 2017 Aug 15;136(7):680-686. DOI: 10.1161/CIRCULATIONAHA.117.029343
  69. 69. Shim WS, Jiang S, Wong P, et al. Ex vivo differentiation of human adult bone marrow stem cells into cardiomyocyte-like cells. Biochemical and Biophysical Research Communications. 2004 Nov 12;324(2):481-488. DOI: 10.1016/j.bbrc.2004.09.087
  70. 70. Yoon J, Min BG, Kim YH, et al. Differentiation, engraftment and functional effects of pre-treated mesenchymal stem cells in a rat myocardial infarct model. Acta Cardiologica. 2005 Jun;60(3):277-284
  71. 71. Bartunek J, Wijns W, Dolatabadi D, Vanderheyden M, Dens J, Ostojic M, Behfar A, Henry S, Tendera M, Waldman S, Terzic A. C-CURE Multicenter Trial: Lineage Specified Bone Marrow Derived Cardiopoietic Mesenchymal Stem Cells for Treatment of Ischemic Cardiomyopathy. Journal of the American College of Cardiology. 2011;57(17):E200
  72. 72. Teerlink JR, Metra M, Filippatos GS, et al. Benefit of cardiopoietic mesenchymal stem cell therapy on left ventricular remodelling: results from the Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) study. European Journal of Heart Failure. 2017 Nov;19(11):1520-1529. DOI: 10.1002/ejhf.898
  73. 73. Wang JS, Shum-Tim D, Galipeau J, et al. Marrow stromal cells for cellular cardiomyoplasty: feasibility and potential clinical advantages. The Journal of thoracic and cardiovascular surgery. 2000 Nov;120(5):999-1005. DOI: 10.1067/mtc.2000.110250
  74. 74. Kamihata H, Matsubara H, Nishiue T, et al. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation. 2001 Aug 28;104(9):1046-1052
  75. 75. Xu M, Wani M, Dai YS, et al. Differentiation of bone marrow stromal cells into the cardiac phenotype requires intercellular communication with myocytes. Circulation. 2004 Oct 26;110(17):2658-2665. DOI: 10.1161/01.CIR.0000145609.20435.36
  76. 76. Li X, Yu X, Lin Q, et al. Bone marrow mesenchymal stem cells differentiate into functional cardiac phenotypes by cardiac microenvironment. Journal of Molecular and Cellular Cardiology. 2007 Feb;42(2):295-303. DOI: 10.1016/j.yjmcc.2006.07.002
  77. 77. Shabbir A, Zisa D, Suzuki G, et al. Heart failure therapy mediated by the trophic activities of bone marrow mesenchymal stem cells: a noninvasive therapeutic regimen. American Journal of Physiology. Heart and Circulatory Physiology. 2009 Jun;296(6):H1888-H1897. DOI: 10.1152/ajpheart.00186.2009
  78. 78. Hatzistergos KE, Saur D, Seidler B, et al. Stimulatory Effects of MSCs on cKit+ Cardiac Stem Cells Are Mediated by SDF1/CXCR4 and SCF/cKit Signaling Pathways. Circulation Research. 2016 Aug 1. DOI: 10.1161/CIRCRESAHA.116.309281
  79. 79. Karantalis V, Suncion-Loescher VY, Bagno L, et al. Synergistic Effects of Combined Cell Therapy for Chronic Ischemic Cardiomyopathy. Journal of the American College of Cardiology. 2015 Nov 3;66(18):1990-1999. DOI: 10.1016/j.jacc.2015.08.879
  80. 80. Leri A, Kajstura J, Anversa P. Role of cardiac stem cells in cardiac pathophysiology: a paradigm shift in human myocardial biology. Circulation Research. 2011 Sep 30;109(8):941-961. DOI: 10.1161/CIRCRESAHA.111.243154 109/8/941 [pii]
  81. 81. Premer C, Blum A, Bellio MA, et al. Allogeneic Mesenchymal Stem Cells Restore Endothelial Function in Heart Failure by Stimulating Endothelial Progenitor Cells. eBioMedicine. 2015;2(5):467-475. DOI: 10.1016/j.ebiom.2015.03.020
  82. 82. Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium. Nature. 2001 Apr 5;410(6829):701-705. DOI: 10.1038/35070587
  83. 83. Karantalis V, Balkan W, Schulman IH, et al. Cell-based therapy for prevention and reversal of myocardial remodeling. American Journal of Physiology. Heart and Circulatory Physiology. 2012 Aug 1;303(3):H256-H270. DOI: 10.1152/ajpheart.00221.2012
  84. 84. Karantalis V, Hare JM. Use of mesenchymal stem cells for therapy of cardiac disease. Circulation Research. 2015 Apr 10;116(8):1413-1430. DOI: 10.1161/CIRCRESAHA.116.303614
  85. 85. Boomsma RA, Geenen DL. Mesenchymal Stem Cells Secrete Multiple Cytokines That Promote Angiogenesis and Have Contrasting Effects on Chemotaxis and Apoptosis. PLoS One. 2012;7(4):e35685. DOI: 10.1371/journal.pone.0035685
  86. 86. Belmokhtar K, Bourguignon T, Worou M, et al. Regeneration of Three Layers Vascular Wall by using BMP2-Treated MSC Involving HIF-1α and Id1 Expressions Through JAK/STAT Pathways. Stem Cell Reviews and Reports. 2011;7(4):847-859. DOI: 10.1007/s12015-011-9254-6
  87. 87. Williams AR, Suncion VY, McCall F, et al. Durable scar size reduction due to allogeneic mesenchymal stem cell therapy regulates whole-chamber remodeling. Journal of the American Heart Association. 2013 Jun;2(3):e000140. DOI: 10.1161/JAHA.113.000140
  88. 88. Toma C, Pittenger MF, Cahill KS, et al. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation. 2002 Jan;105(1, 1):93-98
  89. 89. Karantalis V, Schulman IH, Balkan W, et al. Allogeneic cell therapy: a new paradigm in therapeutics. Circulation Research. 2015 Jan 2;116(1):12-15. DOI: 10.1161/CIRCRESAHA.114.305495
  90. 90. Le Blanc K, Tammik C, Rosendahl K, et al. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Experimental Hematology. 2003 Oct;31(10):890-896
  91. 91. Le Blanc K, Tammik L, Sundberg B, et al. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scandinavian Journal of Immunology. 2003 Jan;57(1):11-20
  92. 92. Klyushnenkova E, Mosca JD, Zernetkina V, et al. T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression. Journal of Biomedical Science. 2005;12(1):47-57. DOI: 10.1007/s11373-004-8183-7
  93. 93. Beyth S, Borovsky Z, Mevorach D, et al. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood. 2005 Mar 1;105(5):2214-2219. DOI: 10.1182/blood-2004-07-2921
  94. 94. de Witte SFH, Luk F, Sierra Parraga JM, et al. Immunomodulation By Therapeutic Mesenchymal Stromal Cells (MSC) Is Triggered Through Phagocytosis of MSC By Monocytic Cells. Stem Cells. 2018 Apr;36(4):602-615. DOI: 10.1002/stem.2779
  95. 95. Majka M, Sulkowski M, Badyra B, et al. Concise Review: Mesenchymal Stem Cells in Cardiovascular Regeneration: Emerging Research Directions and Clinical Applications. Stem Cells Translational Medicine. 2017 Oct;6(10):1859-1867. DOI: 10.1002/sctm.16-0484
  96. 96. Munneke JM, Spruit MJ, Cornelissen AS, et al. The Potential of Mesenchymal Stromal Cells as Treatment for Severe Steroid-Refractory Acute Graft-Versus-Host Disease: A Critical Review of the Literature. Transplantation. 2016 Nov;100(11):2309-2314. DOI: 10.1097/TP.0000000000001029
  97. 97. Boyle AJ, McNiece IK, Hare JM. Mesenchymal stem cell therapy for cardiac repair. Methods in Molecular Biology. 2010;660:65-84. DOI: 10.1007/978-1-60761-705-1_5
  98. 98. Kissel CK, Lehmann R, Assmus B, et al. Selective functional exhaustion of hematopoietic progenitor cells in the bone marrow of patients with postinfarction heart failure. Journal of the American College of Cardiology. 2007 Jun 19;49(24):2341-2349. DOI: 10.1016/j.jacc.2007.01.095
  99. 99. Heiss C, Keymel S, Niesler U, et al. Impaired progenitor cell activity in age-related endothelial dysfunction. Journal of the American College of Cardiology. 2005 May 3;45(9):1441. DOI: 8, S0735-1097(05)00357-8. [pii] 10.1016/j.jacc.2004.12.074
  100. 100. Kovacic JC, Moreno P, Hachinski V, et al. Cellular senescence, vascular disease, and aging: part 1 of a 2-part review. Circulation. 2011 Apr 19;123(15):1650-1660. DOI: 10.1161/CIRCULATIONAHA.110.007021
  101. 101. Ballard VL. Stem cells for heart failure in the aging heart. Heart Failure Reviews. 2010 Sep;15(5):447-456. DOI: 10.1007/s10741-010-9160-z
  102. 102. Yu KR, Kang KS. Aging-related genes in mesenchymal stem cells: a mini-review. Gerontology. 2013;59(6):557-563. DOI: 10.1159/000353857
  103. 103. Raggi C, Berardi AC. Mesenchymal stem cells, aging and regenerative medicine. Muscles, Ligaments and Tendons Journal. 2012 Jul;2(3):239-242
  104. 104. Jones DL, Rando TA. Emerging models and paradigms for stem cell ageing. Nature Cell Biology. 2011 May;13(5):506-512. DOI: 10.1038/ncb0511-506
  105. 105. Li TS, Kubo M, Ueda K, et al. Impaired angiogenic potency of bone marrow cells from patients with advanced age, anemia, and renal failure. The Journal of Thoracic and Cardiovascular Surgery. 2010 Feb;139(2):459-465. DOI: 10.1016/j.jtcvs.2009.07.053
  106. 106. Huang XP, Sun Z, Miyagi Y, et al. Differentiation of allogeneic mesenchymal stem cells induces immunogenicity and limits their long-term benefits for myocardial repair. Circulation. 2010 Dec 7;122(23):2419-2429. DOI: 10.1161/CIRCULATIONAHA.110.955971
  107. 107. Berglund AK, Fortier LA, Antczak DF, et al. Immunoprivileged no more: measuring the immunogenicity of allogeneic adult mesenchymal stem cells. Stem Cell Research & Therapy. 2017 Dec 22;8(1):288. DOI: 10.1186/s13287-017-0742-8
  108. 108. Alcayaga-Miranda F, Cuenca J, Khoury M. Antimicrobial Activity of Mesenchymal Stem Cells: Current Status and New Perspectives of Antimicrobial Peptide-Based Therapies. Frontiers in Immunology. 2017;8:339. DOI: 10.3389/fimmu.2017.00339
  109. 109. Bartunek J, Behfar A, Dolatabadi D, et al. Cardiopoietic Stem Cell Therapy in Heart Failure: The C-CURE (Cardiopoietic stem Cell therapy in heart failURE) Multicenter Randomized Trial With Lineage-Specified Biologics. Journal of the American College of Cardiology. 2013 Jun 11;61(23):2329-2338. DOI: 10.1016/j.jacc.2013.02.071
  110. 110. Kanashiro-Takeuchi RM, Schulman IH, Hare JM. Pharmacologic and genetic strategies to enhance cell therapy for cardiac regeneration. Journal of Molecular and Cellular Cardiology. 2011 Oct;51(4):619-625. DOI: 10.1016/j.yjmcc.2011.05.015
  111. 111. Qayyum AA, Haack-Sorensen M, Mathiasen AB, et al. Adipose-derived mesenchymal stromal cells for chronic myocardial ischemia (MyStromalCell Trial): study design. Regenerative Medicine. 2012 May;7(3):421-428. DOI: 10.2217/rme.12.17
  112. 112. Qayyum AA, Mathiasen AB, Mygind ND, et al. Adipose-Derived Stromal Cells for Treatment of Patients with Chronic Ischemic Heart Disease (MyStromalCell Trial): A Randomized Placebo-Controlled Study. Stem Cells International. 2017;2017:5237063. DOI: 10.1155/2017/5237063
  113. 113. Bartunek J, Terzic A, Davison BA, et al. Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial. European Heart Journal. 2017 Mar 01;38(9):648-660. DOI: 10.1093/eurheartj/ehw543
  114. 114. Tompkins BA, Rieger AC, Florea V, et al. New insights into cell-based therapy for heart failure from the CHART-1 study. European Journal of Heart Failure. 2017 Nov;19(11):1530-1533. DOI: 10.1002/ejhf.955
  115. 115. Karantalis V, Difede DL, Gerstenblith G, et al. Autologous Mesenchymal Stem Cells Produce Concordant Improvements in Regional Function, Tissue Perfusion, and Fibrotic Burden When Administered to Patients Undergoing Coronary Artery Bypass Grafting: The Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) Trial. Circulation Research. 2014 Apr 11;114(8):1302-1310. DOI: 10.1161/CIRCRESAHA.114.303180
  116. 116. Florea V, Rieger AC, DiFede DL, et al. Dose Comparison Study of Allogeneic Mesenchymal Stem Cells in Patients With Ischemic Cardiomyopathy (The TRIDENT Study). Circulation Research. 2017 Nov 10;121(11):1279-1290. DOI: 10.1161/CIRCRESAHA.117.311827
  117. 117. Bolli R, Chugh AR, D'Amario D, et al. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet. 2011 Nov 26;378(9806):1847-1857. DOI: 10.1016/S0140-6736(11)61590-0
  118. 118. Bolli R, Chugh AR, D'Amario D, Loughran JH, Stoddard MF, Ikram S, Wagner SG, Beache GM, Leri A, Hosoda T, Goihberg P, Fiorini C, Solankhi N, Fahsah I, Elmore JB, Rokosh DG, Slaughter MS, Kajstura J, Anversa P. Effect of Cardiac Stem Cells in Patients with Ischemic Cardiomyopathy: Interim Results of the SCIPIO Trial Up to 2 Years After Therapy. Circulation. 2012;126(23):2784
  119. 119. Zhuo Y, Li SH, Chen MS, et al. Aging impairs the angiogenic response to ischemic injury and the activity of implanted cells: combined consequences for cell therapy in older recipients. The Journal of Thoracic and Cardiovascular Surgery 2010 May;139(5):1286-94, 94 e1-2. DOI: 10.1016/j.jtcvs.2009.08.052
  120. 120. Sousa-Victor P, Gutarra S, Garcia-Prat L, et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature. 2014 Feb 12. DOI: 10.1038/nature13013
  121. 121. Geissler S, Textor M, Schmidt-Bleek K, et al. In serum veritas-in serum sanitas? Cell non-autonomous aging compromises differentiation and survival of mesenchymal stromal cells via the oxidative stress pathway. Cell Death & Disease. 2013;4:e970. DOI: 10.1038/cddis.2013.501
  122. 122. Lopez-Otin C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell. 2013 Jun;153(6, 6):1194-1217. DOI: 10.1016/j.cell.2013.05.039
  123. 123. Golpanian S, DiFede DL, Pujol MV, et al. Rationale and design of the allogeneiC human mesenchymal stem cells (hMSC) in patients with aging fRAilTy via intravenoUS delivery (CRATUS) study: A phase I/II, randomized, blinded and placebo controlled trial to evaluate the safety and potential efficacy of allogeneic human mesenchymal stem cell infusion in patients with aging frailty. Oncotarget. 2016 Feb 25. DOI: 10.18632/oncotarget.7727
  124. 124. Li TS, Kubo M, Ueda K, et al. Identification of risk factors related to poor angiogenic potency of bone marrow cells from different patients. Circulation. 2009 Sep 15;120(11 Suppl):S255-S261. DOI: 10.1161/CIRCULATIONAHA.108.837039
  125. 125. Golpanian S, El-Khorazaty J, Mendizabal A, et al. Effect of aging on human mesenchymal stem cell therapy in ischemic cardiomyopathy patients. Journal of the American College of Cardiology. 2015 Jan 20;65(2):125-132. DOI: 10.1016/j.jacc.2014.10.040
  126. 126. Li H, Fan X, Kovi RC, et al. Spontaneous expression of embryonic factors and p53 point mutations in aged mesenchymal stem cells: a model of age-related tumorigenesis in mice. Cancer Research. 2007 Nov 15;67(22):10889-10898. DOI: 10.1158/0008-5472.CAN-07-2665
  127. 127. Rosland GV, Svendsen A, Torsvik A, et al. Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Research. 2009 Jul 1;69(13):5331-5339. DOI: 10.1158/0008-5472.CAN-08-4630
  128. 128. Bernardo ME, Zaffaroni N, Novara F, et al. Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms. Cancer Research. 2007 Oct 1;67(19):9142-9149. DOI: 10.1158/0008-5472.CAN-06-4690
  129. 129. Melzer C, von der Ohe J, Hass R. MSC Cross-Talk with Cancer Cells Provides Therapeutic Potential. Stem Cells. 2018 Mar:31. DOI: 10.1002/stem.2829
  130. 130. Melzer C, von der Ohe J, Hass R. In Vitro Fusion of Normal and Neoplastic Breast Epithelial Cells with Human Mesenchymal Stroma/Stem Cells Partially Involves Tumor Necrosis Factor Receptor Signaling. Stem Cells. 2018 Mar 23. DOI: 10.1002/stem.2819
  131. 131. Tysnes BB, Bjerkvig R. Cancer initiation and progression: involvement of stem cells and the microenvironment. Biochimica et Biophysica Acta. 2007 Jun;1775(2):283-297. DOI: 10.1016/j.bbcan.2007.01.001
  132. 132. Hatzistergos KE, Blum A, Ince T, et al. What is the oncologic risk of stem cell treatment for heart disease? Circulation Research. 2011 May 27;108(11):1300-1303. DOI: 10.1161/CIRCRESAHA.111.246611
  133. 133. Crisostomo PR, Wang M, Herring CM, et al. Gender differences in injury induced mesenchymal stem cell apoptosis and VEGF, TNF, IL-6 expression: role of the 55 kDa TNF receptor (TNFR1). Journal of Molecular and Cellular Cardiology. 2007 Jan;42(1):142-149. DOI: 10.1016/j.yjmcc.2006.09.016
  134. 134. Crisostomo PR, Markel TA, Wang M, et al. In the adult mesenchymal stem cell population, source gender is a biologically relevant aspect of protective power. Surgery. 2007 Aug;142(2):215-221. DOI: 10.1016/j.surg.2007.04.013
  135. 135. Herrmann JL, Abarbanell AM, Weil BR, et al. Gender dimorphisms in progenitor and stem cell function in cardiovascular disease. Journal of Cardiovascular Translational Research. 2010 Apr;3(2):103-113. DOI: 10.1007/s12265-009-9149-y
  136. 136. Erwin GS, Crisostomo PR, Wang Y, et al. Estradiol-treated mesenchymal stem cells improve myocardial recovery after ischemia. The Journal of Surgical Research. 2009 Apr;152(2):319-324. DOI: 10.1016/j.jss.2008.02.006
  137. 137. Katritsis DG, Sotiropoulou PA, Karvouni E, et al. Transcoronary transplantation of autologous mesenchymal stem cells and endothelial progenitors into infarcted human myocardium. Catheterization and Cardiovascular Interventions. 2005 Jul;65(3):321-329. DOI: 10.1002/ccd.20406
  138. 138. Chen SL, Fang WW, Ye F, et al. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. The American Journal of Cardiology. 2004 Jul;94(1, 1):92-95. DOI: 10.1016/j.amjcard.2004.03.034
  139. 139. Suncion VY, Ghersin E, Fishman JE, et al. Does Transendocardial Injection of Mesenchymal Stem Cells Improve Myocardial Function Locally or Globally?: An Analysis From the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis (POSEIDON) Randomized Trial. Circulation Research. 2014 Apr 11;114(8):1292-1301. DOI: 10.1161/CIRCRESAHA.114.302854
  140. 140. Mathiasen AB, Qayyum AA, Jorgensen E, et al. Bone marrow-derived mesenchymal stromal cell treatment in patients with severe ischaemic heart failure: a randomized placebo-controlled trial (MSC-HF trial). European Heart Journal. 2015 Jul 14;36(27):1744-1753. DOI: 10.1093/eurheartj/ehv136
  141. 141. Bartolucci J, Verdugo FJ, Gonzalez PL, et al. Safety and Efficacy of the Intravenous Infusion of Umbilical Cord Mesenchymal Stem Cells in Patients With Heart Failure: A Phase 1/2 Randomized Controlled Trial (RIMECARD Trial [Randomized Clinical Trial of Intravenous Infusion Umbilical Cord Mesenchymal Stem Cells on Cardiopathy]). Circulation Research. 2017 Oct 27;121(10):1192-1204. DOI: 10.1161/CIRCRESAHA.117.310712
  142. 142. Williams AR, Trachtenberg B, Velazquez DL, et al. Intramyocardial stem cell injection in patients with ischemic cardiomyopathy: functional recovery and reverse remodeling. Circulation Research. 2011 Apr 1;108(7):792-796. DOI: 10.1161/CIRCRESAHA.111.242610
  143. 143. Mathiasen AB, Haack-Sorensen M, Jorgensen E, et al. Autotransplantation of mesenchymal stromal cells from bone-marrow to heart in patients with severe stable coronary artery disease and refractory angina--final 3-year follow-up. International Journal of Cardiology. 2013 Dec 10;170(2):246-251. DOI: 10.1016/j.ijcard.2013.10.079
  144. 144. Jansen Of Lorkeers SJ, Eding JE, Vesterinen HM, et al. Similar effect of autologous and allogeneic cell therapy for ischemic heart disease: systematic review and meta-analysis of large animal studies. Circulation Research. 2015 Jan 2;116(1):80-86. DOI: 10.1161/circresaha.116.304872
  145. 145. Chullikana A, Majumdar AS, Gottipamula S, et al. Randomized, double-blind, phase I/II study of intravenous allogeneic mesenchymal stromal cells in acute myocardial infarction. Cytotherapy. 2015 Mar;17(3):250-261. DOI: 10.1016/j.jcyt.2014.10.009
  146. 146. Penn MS, Ellis S, Gandhi S, et al. Adventitial delivery of an allogeneic bone marrow-derived adherent stem cell in acute myocardial infarction: phase I clinical study. Cir-culation Research. 2012 Jan 20;110(2):304-311. DOI: 10.1161/CIRCRESAHA.111.253427
  147. 147. Suncion VY, Ghersin E, Fishman J, et al. Does Transendocardial Injection of Mesenchymal Stem Cells Improve Myocardial Function Locally or Globally? An Analysis From the POSEIDON Randomized Trial. Circulation Research. 2014 Jan 21. DOI: 10.1161/CIRCRESAHA.114.302854
  148. 148. Kanelidis AJ, Premer C, Lopez J, et al. Route of Delivery Modulates the Efficacy of Mesenchymal Stem Cell Therapy for Myocardial Infarction: A Meta-Analysis of Pre-clinical Studies and Clinical Trials. Circulation Research. 2017 Mar 31;120(7):1139-1150. DOI: 10.1161/CIRCRESAHA.116.309819
  149. 149. Golpanian S, Schulman IH, Ebert RF, et al. Concise Review: Review and Perspective of Cell Dosage and Routes of Administration From Preclinical and Clinical Studies of Stem Cell Therapy for Heart Disease. Stem Cells Translational Medicine. 2015 Dec 18. DOI: 10.5966/sctm.2015-0101
  150. 150. Hare JM, Bolli R, Cooke JP, et al. Phase II clinical research design in cardiology: learning the right lessons too well: observations and recommendations from the Cardiovascular Cell Therapy Research Network (CCTRN). Circulation. 2013 Apr 16;127(15):1630-1635. DOI: 10.1161/CIRCULATIONAHA.112.000779
  151. 151. Schulman IH BW, Saltzman R, DaFonseca D, Caceres L, Delgado C, Pujol M, Ramdas K, Tovar J, Vidro-Casiano M, Hare JM. Unique Aspects of the Design of Phase I/II Clinical Trials of Stem Cell Therapy. In: The Management of Clinical Trials [Internet]. InTech; 2017
  152. 152. Fernandez-Aviles F, Sanz-Ruiz R, Climent AM, et al. Global position paper on cardiovascular regenerative medicine. European Heart Journal. 2017 Sep 01;38(33):2532-2546. DOI: 10.1093/eurheartj/ehx248
  153. 153. Butler J, Epstein SE, Greene SJ, et al. Intravenous Allogeneic Mesenchymal Stem Cells for Nonischemic Cardiomyopathy: Safety and Efficacy Results of a Phase II-A Randomized Trial. Circulation Research. 2017 Jan 20;120(2):332-340. DOI: 10.1161/CIRCRESAHA.116.309717
  154. 154. Vertelov G, Kharazi L, Muralidhar MG, et al. High targeted migration of human mesenchymal stem cells grown in hypoxia is associated with enhanced activation of RhoA. Stem Cell Research & Therapy. 2013 January 07;4(1):5. DOI: 10.1186/scrt153
  155. 155. Zhao XF, Xu Y, Zhu ZY, et al. Clinical observation of umbilical cord mesenchymal stem cell treatment of severe systolic heart failure. Genetics and Molecular Research. 2015 Apr 10;14(2):3010-3017. DOI: 10.4238/2015.April.10.11
  156. 156. Schulman IH, Zhou MS. Vascular insulin resistance: a potential link between cardiovascular and metabolic diseases. Current Hypertension Reports. 2009 Feb;11(1):48-55
  157. 157. Schulman IH, Zhou MS, Raij L. Interaction between nitric oxide and angiotensin II in the endothelium: role in atherosclerosis and hypertension. Journal of hypertension Supplement: official journal of the International Society of Hypertension. 2006 Mar;24(1):S45-S50. DOI: 10.1097/01.hjh.0000220406.46246.f2
  158. 158. Marti CN, Gheorghiade M, Kalogeropoulos AP, et al. Endothelial dysfunction, arterial stiffness, and heart failure. Journal of the American College of Cardiology. 2012 Oct;60(16, 16):1455-1469. DOI: 10.1016/j.jacc.2011.11.082
  159. 159. Werner N, Wassmann S, Ahlers P, et al. Endothelial progenitor cells correlate with endothelial function in patients with coronary artery disease. Basic Research in Cardiology. 2007 Nov;102(6):565-571. DOI: 10.1007/s00395-007-0680-1
  160. 160. Eleuteri E, Di Stefano A, Tarro Genta F, et al. Stepwise increase of angiopoietin-2 serum levels is related to haemodynamic and functional impairment in stable chronic heart failure. European Journal Of Cardiovascular Prevention And Rehabilitation: Official Jour-nal Of The European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology. 2011 Aug;18(4):607-614. DOI: 10.1177/1741826710389410
  161. 161. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics--2015 update: a report from the American Heart Association. Circulation. 2015 Jan 27;131(4):e29-e322. DOI: 10.1161/CIR.0000000000000152
  162. 162. Kim JA, Montagnani M, Koh KK, et al. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation. 2006 Apr 18;113(15):1888-1904. DOI: 10.1161/CIRCULATIONAHA.105.563213
  163. 163. Zhou MS, Schulman IH, Zeng Q. Link between the renin-angiotensin system and insulin resistance: implications for cardiovascular disease. Vascular Medicine. 2012 Oct;17(5):330-341. DOI: 10.1177/1358863X12450094
  164. 164. Perin EC, Murphy MP, March KL, et al. Evaluation of Cell Therapy on Exercise Per-formance and Limb Perfusion in Peripheral Artery Disease: The CCTRN Patients with Intermittent Claudication Injected with ALDH Bright Cells (PACE) Trial. Circulation. 2017 Feb 16. DOI: 10.1161/CIRCULATIONAHA.116.025707
  165. 165. Griffin MD, Ritter T, Mahon BP. Immunological aspects of allogeneic mesenchymal stem cell therapies. Human Gene Therapy. 2010 Dec;21(12):1641-1655. DOI: 10.1089/hum.2010.156
  166. 166. Tse WT, Pendleton JD, Beyer WM, et al. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation. 2003 Feb 15;75(3):389-397. DOI: 10.1097/01.TP.0000045055.63901.A9
  167. 167. Krampera M, Cosmi L, Angeli R, et al. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells. 2006 Feb;24(2):386-398. DOI: 10.1634/stemcells.2005-0008
  168. 168. Ren G, Zhang L, Zhao X, et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell. 2008 Feb 7;2(2):141-150. DOI: S1934-5909(07)00314-1 [pii] 10.1016/j.stem.2007.11.014
  169. 169. Chabannes D, Hill M, Merieau E, et al. A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells. Blood. 2007 Nov 15;110(10):3691-3694. DOI: blood-2007-02-075481 [pii] 10.1182/blood-2007-02-075481
  170. 170. Sato K, Ozaki K, Oh I, et al. Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood. 2007 Jan;109(1, 1):228-234. DOI: 10.1182/blood-2006-02-002246
  171. 171. Raffaghello L, Bianchi G, Bertolotto M, et al. Human mesenchymal stem cells inhibit neutrophil apoptosis: a model for neutrophil preservation in the bone marrow niche. Stem Cells. 2008 Jan;26(1):151-162. DOI: 10.1634/stemcells.2007-0416
  172. 172. Jiang XX, Zhang Y, Liu B, et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood. 2005 May 15;105(10):4120-4126. DOI: 10.1182/blood-2004-02-0586
  173. 173. Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002 May 15;99(10):3838-3843
  174. 174. Duffy MM, Ritter T, Ceredig R, et al. Mesenchymal stem cell effects on T-cell effector pathways. Stem Cell Research & Therapy. 2011;2(4):34. DOI: 10.1186/scrt75
  175. 175. Casiraghi F, Perico N, Remuzzi G. Mesenchymal stromal cells to promote solid organ transplantation tolerance. Current Opinion in Organ Transplantation. 2013 Feb;18(1):51-58. DOI: 10.1097/MOT.0b013e32835c5016
  176. 176. Baron F, Lechanteur C, Willems E, et al. Cotransplantation of mesenchymal stem cells might prevent death from graft-versus-host disease (GVHD) without abrogating graft-versus-tumor effects after HLA-mismatched allogeneic transplantation following nonmyeloablative conditioning. Biology of Blood and Marrow Transplantation. 2010 Jun;16(6):838-847. DOI: 10.1016/j.bbmt.2010.01.011
  177. 177. Gonzalo-Daganzo R, Regidor C, Martin-Donaire T, et al. Results of a pilot study on the use of third-party donor mesenchymal stromal cells in cord blood transplantation in adults. Cytotherapy. 2009;11(3):278-288. DOI: 10.1080/14653240902807018
  178. 178. Riella Lv CA. STem cell therapy in kidney transplantation. Journal of the American Medical Association. 2012;308(2):130-131. DOI: 10.1001/jama.2012.6370
  179. 179. Tan JPARC. STem cell therapy in kidney transplantation—reply. Journal of the American Medical Association. 2012;308(2):130-131. DOI: 10.1001/jama.2012.6372
  180. 180. Casiraghi F, Remuzzi G, Abbate M, et al. Multipotent mesenchymal stromal cell therapy and risk of malignancies. Stem Cell Reviews. 2013 Feb;9(1):65-79. DOI: 10.1007/s12015-011-9345-4
  181. 181. Detry O, Vandermeulen M, Delbouille MH, et al. Infusion of mesenchymal stromal cells after deceased liver transplantation: A phase I-II, open-label, clinical study. Journal of Hepatology. 2017 Jul;67(1):47-55. DOI: 10.1016/j.jhep.2017.03.001
  182. 182. Casiraghi F, Azzollini N, Todeschini M, et al. Localization of mesenchymal stromal cells dictates their immune or proinflammatory effects in kidney transplantation. American Journal of Transplantation. 2012 Sep;12(9):2373-2383. DOI: 10.1111/j.1600-6143.2012.04115.x
  183. 183. Farris AB, Taheri D, Kawai T, et al. Acute renal endothelial injury during marrow recovery in a cohort of combined kidney and bone marrow allografts. American Journal of Transplantation. 2011 Jul;11(7):1464-1477. DOI: 10.1111/j.1600-6143.2011.03572.x
  184. 184. Perico N, Casiraghi F, Introna M, et al. Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility. Clinical Journal of the American Society of Nephrology: CJASN. 2011 Feb;6(2):412-422. DOI: 10.2215/CJN.04950610
  185. 185. Berman DM, Willman MA, Han D, et al. Mesenchymal Stem Cells Enhance Allogeneic Islet Engraftment in Nonhuman Primates. Diabetes. 2010;59(10):2558-2568. DOI: 10.2337/db10-0136
  186. 186. Uccelli A, Laroni A, Freedman MS. Mesenchymal stem cells as treatment for MS - progress to date. Multiple Sclerosis. 2013 Apr;19(5):515-519. DOI: 10.1177/1352458512464686
  187. 187. Llufriu S, Sepulveda M, Blanco Y, et al. Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis. PLoS One. 2014;9(12):e113936. DOI: 10.1371/journal.pone.0113936
  188. 188. Duijvestein M, Vos AC, Roelofs H, et al. Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn's disease: results of a phase I study. Gut. 2010 Dec;59(12):1662-1669. DOI: 10.1136/gut.2010.215152
  189. 189. Ciccocioppo R, Bernardo ME, Sgarella A, et al. Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn's disease. Gut. 2011 Jun;60(6):788-798. DOI: 10.1136/gut.2010.214841
  190. 190. Forbes GM, Sturm MJ, Leong RW, et al. A Phase 2 Study of Allogeneic Mesenchymal Stromal Cells for Luminal Crohn's Disease Refractory to Biologic Therapy. Clinical Gastroenterology and Hepatology. 2014;12(1):64-71. DOI: 10.1016/j.cgh.2013.06.021
  191. 191. Molendijk I, Bonsing BA, Roelofs H, et al. Allogeneic Bone Marrow&#x2013;Derived Mesenchymal Stromal Cells Promote Healing of Refractory Perianal Fistulas in Patients With Crohn’s Disease. Gastroenterology. 2015;149(4):918-27.e6. DOI: 10.1053/j.gastro.2015.06.014
  192. 192. Gu F, Wang D, Zhang H, et al. Allogeneic mesenchymal stem cell transplantation for lupus nephritis patients refractory to conventional therapy. Clinical Rheumatology. 2014 November 01;33(11):1611-1619. DOI: 10.1007/s10067-014-2754-4
  193. 193. Wang D, Li J, Zhang Y, et al. Umbilical cord mesenchymal stem cell transplantation in active and refractory systemic lupus erythematosus: a multicenter clinical study. Arthritis Research & Therapy. 2014 March 25;16(2):R79. DOI: 10.1186/ar4520
  194. 194. Zheng ZH, Li XY, Ding J, et al. Allogeneic mesenchymal stem cell and mesenchymal stem cell-differentiated chondrocyte suppress the responses of type II collagen-reactive T cells in rheumatoid arthritis. Rheumatology (Oxford, England). 2008 Jan;47(1):22-30. DOI: 10.1093/rheumatology/kem284
  195. 195. Chen FH, Tuan RS. Mesenchymal stem cells in arthritic diseases. Arthritis Research & Therapy. 2008;10(5):223. DOI: 10.1186/ar2514
  196. 196. Sims E, Evans-Molina C. Stem cells as a tool to improve outcomes of islet transplantation. Journal of Transplantation. 2012;2012:736491. DOI: 10.1155/2012/736491
  197. 197. Ezquer FE, Ezquer ME, Parrau DB, et al. Systemic administration of multipotent mesenchymal stromal cells reverts hyperglycemia and prevents nephropathy in type 1 diabetic mice. Biology of Blood and Marrow Transplantation. 2008 Jun;14(6):631-640. DOI: 10.1016/j.bbmt.2008.01.006
  198. 198. Chao KC, Chao KF, Fu YS, et al. Islet-like clusters derived from mesenchymal stem cells in Wharton's Jelly of the human umbilical cord for transplantation to control type 1 diabetes. PLoS One. 2008;3(1):e1451. DOI: 10.1371/journal.pone.0001451
  199. 199. Xie QP, Huang H, Xu B, et al. Human bone marrow mesenchymal stem cells differentiate into insulin-producing cells upon microenvironmental manipulation in vitro. Differentiation; Research in Biological Diversity. 2009 Jun;77(5):483-491. DOI: 10.1016/j.diff.2009.01.001
  200. 200. Park KS, Kim YS, Kim JH, et al. Trophic molecules derived from human mesenchymal stem cells enhance survival, function, and angiogenesis of isolated islets after transplantation. Transplantation. 2010 Mar 15;89(5):509-517. DOI: 10.1097/TP.0b013e3181c7dc99
  201. 201. Cai J, Wu Z, Xu X, et al. Umbilical cord mesenchymal stromal cell with autologous bone marrow cell transplantation in established type 1 diabetes: a pilot randomized controlled open-label clinical study to assess safety and impact on insulin secretion. Diabetes Care. 2016;39(1):149-157. DOI: 10.2337/dc15-0171
  202. 202. Carlsson P-O, Schwarcz E, Korsgren O, et al. Preserved β-Cell Function in Type 1 Diabetes by Mesenchymal Stromal Cells. Diabetes. 2015;64(2):587-592. DOI: 10.2337/db14-0656
  203. 203. Toonkel RL, Hare JM, Matthay MA, et al. Mesenchymal Stem Cells and Idiopathic Pulmonary Fibrosis: Potential for Clinical Testing. American Journal of Respiratory and Critical Care Medicine. 2013 Jan 12. DOI: 10.1164/rccm.201207-1204PP
  204. 204. Kajstura J, Rota M, Hall SR, et al. Evidence for human lung stem cells. The New England Journal of Medicine. 2011 May 12;364(19):1795-1806. DOI: 10.1056/NEJMoa1101324
  205. 205. Wu Y, Chen L, Scott PG, et al. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells. 2007 Oct;25(10):2648-2659. DOI: 10.1634/stemcells.2007-0226
  206. 206. Rodriguez-Menocal L, Salgado M, Ford D, et al. Stimulation of skin and wound fibroblast migration by mesenchymal stem cells derived from normal donors and chronic wound patients. Stem Cells Translational Medicine. 2012 Mar;1(3):221-229. DOI: 10.5966/sctm.2011-0029
  207. 207. Clover AJ, Kumar AH, Isakson M, et al. Allogeneic mesenchymal stem cells, but not culture modified monocytes, improve burn wound healing. Burns: journal of the International Society for Burn Injuries. 2014 Sep 15. DOI: 10.1016/j.burns.2014.08.009
  208. 208. Liu L, Yu Y, Hou Y, et al. Human umbilical cord mesenchymal stem cells transplantation promotes cutaneous wound healing of severe burned rats. PLoS One. 2014;9(2):e88348. DOI: 10.1371/journal.pone.0088348
  209. 209. Xue L, Xu YB, Xie JL, et al. Effects of human bone marrow mesenchymal stem cells on burn injury healing in a mouse model. International Journal of Clinical and Experimental Pathology. 2013;6(7):1327-1336
  210. 210. Paul G, Anisimov SV. The secretome of mesenchymal stem cells: potential implications for neuroregeneration. Biochimie. 2013 Dec;95(12):2246-2256. DOI: 10.1016/j.biochi.2013.07.013
  211. 211. Oliveri RS, Bello S, Biering-Sorensen F. Mesenchymal stem cells improve locomotor recovery in traumatic spinal cord injury: Systematic review with meta-analyses of rat models. Neurobiology of Disease. 2013 Oct 19. DOI: 10.1016/j.nbd.2013.10.014
  212. 212. Neirinckx V, Coste C, Rogister B, et al. Concise review: adult mesenchymal stem cells, adult neural crest stem cells, and therapy of neurological pathologies: a state of play. Stem Cells Translational Medicine. 2013 Apr;2(4):284-296. DOI: 10.5966/sctm.2012-0147
  213. 213. Hess DC, Wechsler LR, Clark WM, et al. Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): a randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet Neurology. 2017;16(5):360-8. DOI: 10.1016/S1474-4422(17)30046-7
  214. 214. Marei HE, Hasan A, Rizzi R, et al. Potential of Stem Cell-Based Therapy for Ischemic Stroke. Frontiers in Neurology. 2018;9:34
  215. 215. Hayashi T, Wakao S, Kitada M, et al. Autologous mesenchymal stem cell-derived dopaminergic neurons function in parkinsonian macaques. J Clin Invest. 2013 Jan 2;123(1):272-84. DOI: 10.1172/JCI62516
  216. 216. Glavaski-Joksimovic A, Bohn MC. Mesenchymal stem cells and neuroregeneration in Parkinson’s disease. Exp Neurol. 2013 Sep;247:25-38. DOI: 10.1016/j.expneurol.2013.03.016
  217. 217. Zhang R, Liu Y, Yan K, et al. Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury. Journal of neuroinflammation. 2013;10(1):106. DOI: 10.1186/1742-2094-10-106
  218. 218. Wang S, Cheng H, Dai G, et al. Umbilical cord mesenchymal stem cell transplantation significantly improves neurological function in patients with sequelae of traumatic brain injury. Brain research. 2013 Sep 26;1532:76-84. DOI: 10.1016/j.brainres.2013.08.001
  219. 219. Liu R, Zhang Z, Lu Z, et al. Human umbilical cord stem cells ameliorate experimental autoimmune encephalomyelitis by regulating immunoinflammation and remyelination. Stem Cells Dev. 2013 Apr 1;22(7):1053-62. DOI: 10.1089/scd.2012.0463
  220. 220. Scolding NJ, Pasquini M, Reingold SC, et al. Cell-based therapeutic strategies for multiple sclerosis. Brain : a journal of neurology. 2017 Nov 1;140(11):2776-96. DOI: 10.1093/brain/awx154
  221. 221. Wilkins A, Kemp K, Ginty M, et al. Human bone marrow-derived mesenchymal stem cells secrete brain-derived neurotrophic factor which promotes neuronal survival in vitro. Stem cell research. 2009 Jul;3(1):63-70. DOI: 10.1016/j.scr.2009.02.006
  222. 222. Wang J, Bian C, Liao L, et al. Inhibition of hepatic stellate cells proliferation by mesenchymal stem cells and the possible mechanisms. Hepatology research : the official journal of the Japan Society of Hepatology. 2009 Dec;39(12):1219-28. DOI: 10.1111/j.1872-034X.2009.00564.x
  223. 223. Nasir GA, Mohsin S, Khan M, et al. Mesenchymal stem cells and Interleukin-6 attenuate liver fibrosis in mice. Journal of translational medicine. 2013;11:78. DOI: 10.1186/1479-5876-11-78
  224. 224. Li Q, Zhou X, Shi Y, et al. In vivo tracking and comparison of the therapeutic effects of MSCs and HSCs for liver injury. PloS one. 2013;8(4):e62363. DOI: 10.1371/journal.pone.0062363
  225. 225. Chang YJ, Liu JW, Lin PC, et al. Mesenchymal stem cells facilitate recovery from chemically induced liver damage and decrease liver fibrosis. Life sciences. 2009 Sep 23;85(13-14):517-25. DOI: 10.1016/j.lfs.2009.08.003
  226. 226. Wang Y, Lian F, Li J, et al. Adipose derived mesenchymal stem cells transplantation via portal vein improves microcirculation and ameliorates liver fibrosis induced by CCl4 in rats. Journal of translational medicine. 2012;10:133. DOI: 10.1186/1479-5876-10-133
  227. 227. Jung KH, Shin HP, Lee S, et al. Effect of human umbilical cord blood-derived mesenchymal stem cells in a cirrhotic rat model. Liver international : official journal of the International Association for the Study of the Liver. 2009 Jul;29(6):898-909. DOI: 10.1111/j.1478-3231.2009.02031.x
  228. 228. Shi M, Zhang Z, Xu R, et al. Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients. Stem cells translational medicine. 2012 Oct;1(10):725-31. DOI: 10.5966/sctm.2012-0034
  229. 229. Zhang Z, Lin H, Shi M, et al. Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients. Journal of gastroenterology and hepatology. 2012 Mar;27(Suppl 2):112-20. DOI: 10.1111/j.1440-1746.2011.07024.x
  230. 230. Wang L, Li J, Liu H, et al. Pilot study of umbilical cord-derived mesenchymal stem cell transfusion in patients with primary biliary cirrhosis. Journal of gastroenterology and hepatology. 2013 Aug;28(Suppl 1):85-92. DOI: 10.1111/jgh.12029
  231. 231. Jang YO, Kim YJ, Baik SK, et al. Histological improvement following administration of autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: a pilot study. Liver international : official journal of the International Association for the Study of the Liver. 2014 Jan;34(1):33-41. DOI: 10.1111/liv.12218
  232. 232. Alfaifi M, Eom YW, Newsome PN, et al. Mesenchymal stromal cell therapy for liver diseases. Journal of hepatology. 2018;68(6):1272-85. DOI: 10.1016/j.jhep.2018.01.030
  233. 233. Mohamadnejad M, Alimoghaddam K, Mohyeddin-Bonab M, et al. Phase 1 trial of autologous bone marrow mesenchymal stem cell transplantation in patients with decompensated liver cirrhosis. Archives of Iranian medicine. 2007 Oct;10(4):459-66. DOI: 07104/AIM.008
  234. 234. Golpanian S, DiFede DL, Khan A, et al. Allogeneic Human Mesenchymal Stem Cell Infusions for Aging Frailty. J Gerontol A Biol Sci Med Sci. 2017 Oct 12;72(11):1505-12. DOI: 10.1093/gerona/glx056
  235. 235. Golpanian S, DiFede DL, Pujol MV, et al. Rationale and design of the allogeneiC human mesenchymal stem cells (hMSC) in patients with aging fRAilTy via intravenoUS delivery (CRATUS) study: A phase I/II, randomized, blinded and placebo controlled trial to evaluate the safety and potential efficacy of allogeneic human mesenchymal stem cell infusion in patients with aging frailty. Oncotarget. 2016 Mar 15;7(11):11899-912. DOI: 10.18632/oncotarget.7727
  236. 236. Hare JM, Bolli R, Cooke JP, et al. Phase II Clinical Research Design in Cardiology: Learning the Right Lessons Too Well: Observations and Recommendations From the Cardiovascular Cell Therapy Research Network (CCTRN). Circulation. 2013 Apr 16;127(15):1630-5. DOI: 10.1161/CIRCULATIONAHA.112.000779

Written By

Ivonne Hernandez Schulman and Joshua M. Hare

Submitted: December 6th, 2017 Reviewed: May 10th, 2018 Published: November 5th, 2018