Sources, basic features and therapeutic indications of MSCs
Mesenchymal stem cells (MSCs) are heterogeneous progenitor cells that have the capacity of self-renewal and multi-lineage differentiation. These adult stem cells can be derived from several sources including bone marrow (BM), peripheral blood, cord blood, placenta, amniotic fluid, skin and adipose tissue. They have certain distinguishing features and their immunomodulatory and immunosuppressive properties enable them to have several therapeutic and clinical applications. Recently, MSCs have gained enormous potential as they can potentially cure various intractable and chronic diseases and as they have shown effectiveness in the treatment of various infections in animal models and in early clinical trials. MSCs are essential constituents of the framework that supports organ integrity and tissue barriers. Suppression of both T and B cells allows them to be major players in the innate response to bacterial infection and in controlling inflammatory response. Human BM-MSCs possess direct antibacterial activity against Gram-negative bacilli and they have been shown to improve survival and reduce mortality in animal models having septic complications. BM-MSCs are effective in treating sepsis and acute respiratory distress syndrome in high-risk patients such as those with malignant hematological disorders, recipients of solid organ and hematopoietic stem cell transplantation (HSCT) and patients receiving advanced level of care in intensive care units. Additionally, human BM-MSCs can act as drug delivery vehicles by enhancing the effectiveness of conventional antimicrobials and thus they may prevent the evolution of drug-resistant microbes. MSCs contain a subset of interleukin-17+ that is capable of inhibiting the growth of Candida albicans (C. albicans). Also, CD 271+ BM-MSCs may provide a long-term protective intracellular niche in the host where Mycobacterium tuberculosis (M.TB) organisms remain viable but in a dormant state. Two recent clinical trials in humans that included 57 patients have shown that autologous transplantation of MSCs can successfully treat multidrug resistant (MDR) strains of M.TB. Animal studies have demonstrated that MSCs enhance host defenses against malaria. MSC therapy improves liver function and promotes hepatocellular regeneration in patients with hepatic fibrosis caused by schistosomiasis. Transplantation of MSCs has been shown to reverse right ventricular dilatation, cardiomyopathy and advanced cardiac involvement caused by Trypanosoma cruzi infection.
- Mesenchymal stem cells
- Bone marrow
- Wharton's jelly
- Multidrug resistance
Mesenchymal stem cells (MSCs) - also called fibroblastoid cells, giant fat cells with blanket cells, spindle-shaped flattened cells or very small round cells - have an inherent ability of self-renewal, proliferation and differentiation toward mature tissues depending on the surrounding microenvironment [1, 2]. Such characteristic, intrinsic to stem cells, makes MSC very attractive for utilization in cell therapy and regenerative medicine . The discovery of MSCs can be dated to the 1960s and can be credited to the work of AJ Friedenstein during which he observed that bone marrow (BM) is the source of MSCs in postnatal life .
MSCs comprise only a tiny fraction of BM and other tissues. BM-derived MSCs [BM-MSCs] constitute 0.0001% to 0.01% of all nucleated BM cells . Adipose tissues contain 100, 000 MSCs in each gram of fat. Adipose tissue-derived MSCs (AT-MSCs) represent an attractive cell source for stem cell therapy. Transplantation of up to 2x108 cells / kg of autologous human adipose tissue-derived MSCs may be safe when given by slow intravenous infusion . The sources of MSCs, their distinguishing features and their therapeutic indications are included in Table 1 [1-4].
|1- Bone marrow
2- Peripheral blood
3- Blood of umbilical cord
4- Amniotic fluid
5- Synovial fluid
6- Dental tissues e.g. pulp
7- Palatal tonsil
8- Fallopian tubes
9- Fat: adipose tissue
10- Parathyroid glands
|(A) They must be plastic adherent
(B) They must be capable of
(C) Findings on flowcytometry:
 positive surface molecules:
- CD 105
- CD 73
- CD 90
 negative surface molecules:
- CD 45
- CD 34
- CD 14
- CD 11
- CD 19
- CD 79
- HLA - DR
|1- In stem cell transplantation:
- Prevention and treatment of graft versus
- Enhancement of engraftment
2- In cardiology; treatment of:
- Coronary artery disease
- Myocardial infarction
- Dilated cardiomyopathy
3- Critical limb ischemia
4- Repair of skeletal tissues
5- Non-healing chronic wounds
6- Chronic spinal cord injuries
7- Liver injury
8- Regenerative medicine
9- Osteogenesis imperfecta
10- Amyotrophic lateral sclerosis
11- Acute respiratory distress syndrome
12- Severe autoimmune disorders: systemic lupus erythromatosis, rheumatoid arthritis, multiple sclerosis and systemic sclerosis
|Hau SR et al
|- MSCs harvested from
compact bone of mice
- Intravenous injection of
MSCs into tail veins
- CLP, in vivo method
- Polymicrobial sepsis
|- Increased survival of mice
- Decreased organ injury
- Increased neutrophil phagocytosis
- Decreased circulating bacteria
|Mei SHJ et al
|- Bone Marrow-MSCs
- Intravenous administration
- In vivo method
|- Significant reduction in mortality in septic mice
receiving appropriate anti-microbial therapy.
- Significant increase in bacterial clearance partly
due to increased phagocytic activity of host
|Luo CT et al
|- Bone marrow-MSCs
- Intravenous administration
- Polymicrobial sepsis
|- Decreased circulating bacteria
- Alleviation of sepsis - related acute kidney injury
- Improved survival of mice.
- Inhibition of IL-17 secretion
- After MSC therapy, the following interleukins and inflammatory mediators were reduced in kidney tissues: Il-6, IL-7, TNF-α, INF-γ, CXCL1, CXCL2, CXCL5, CCL2 and CCL3
|Gupta N et al
|- Bone marrow - MSCs
- Intratracheal injection
- Unstimulated mouse MSCs
- In vitro study
|- Increased survival of mice
- Inhibition of bacterial growth
- Increased lipocalin-2 in bronchoalvealar lavage fluid.
- Increased phagocytic activity
|Nemeth K et al
|- Bone marrow - MSCs
- Activated MSCs
- In vivo study
|- Reduced mortality of mice
- Improved organ function
- The beneficial effects of MSCs were eliminated by:
macrophage depletion or pre-treat-IL-10 receptors.
- MSCs reprogram macrophages by releasing postaglandin E2.
Rey et al
|- Human and murine
- Intraperitoneal injection
- CLP and endotoxin injection
- Colitis and sepsis model, in vivo study
|- Systemic infusion of adipose tissue-derived MSCs resulted in:
increased survival of mice in addition to significant amelioration of severity
of colitis and sepsis.
|- Apoptotic adipose tissue- MSCs
- Rat model
- Penile venous transfusion
- Peritoneal sepsis, acute kidney injury
|- Protection of major organs from damage
- Improved prognosis and reduced mortality of animals treated with MSCs.
- Increased circulating levels of TNF-γ
- Reduction in the numbers of: helper and cytotoxic T-cells, T-regulatory cells in peripheral blood and spleens of animals.
|Yang R et al
|- IL-17 producing MSCs||- Inhibition of growth of
- Mechanism of action: stimulation of IL-17 production.
|- Rat model
- Adipose tissue - MSCs
- Sepsis syndrome, kidney and lung injury
|- Adipose tissue MSC therapy was superior to healthy adipose-derived MSC therapy in preventing major organ damage in rats treated with CLP-induced sepsis syndrome.|
R et al
|- Human MSCs
- Interferon –γ stimulated MSCs
- In vitro study
|- Inhibition of gram-positive bacteria
- Inhibition of intracellular CMV and HSV-1 replication
- Increased indoleamine -2,3- dioxygenase
|Krasnodembskaya A et al
|- Human BM-MSCs murine model
- Intravenous admin istration of MSCs
|- Increased antimicrobial activity and decreased bacterial growth in bronchoalveolar lavage.
- Decrease in lung bacterial load.
- Inhibition of bacterial growth in vitro
- IV MSCs + neutralizing antibodies to IL-37: reduced bacterial clearance.
|Krasnodembskaya A et al
|- Human BM - MSCs
- Intravenous administration
- Murine Gram-negative
|- Increased survival due to increased clearance of bacteria
-Increased phagocytic activity of mononuclear cells in spleens of mice.
- Marked reduction in circulating bacteria in the blood of treated mice.
- Increased number of platelets inhibitor -1 (PAI-1)
- No change in cytokine levels in plasma and peritoneal fluid.
|Kim ES et al
|- Human umbilical cord blood - MSCs
- Intrathecal administration
- E. coli induced acute lung injury
- In vivo study in mice
|- Increased survival of treated mice
- Reduced bacterial burden in pneumonia model.
- Acute lung injury induced by
down-modulation of inflammatory process and enhancement
of bacterial clearance
- Anti-inflammatory mechanisms involved.
|Casatella MA et al
|- Human MSCs
- In vitro study
|- Enhancement of neutrophil function
- Proposed mechanisms: IL- 6, INF- β and GM-CSF
|Maqbool M et al
|- Human MSCs
- In vitro study
|- Inhibition of neutrophil apoptosis
- Unknown mechanism of action
- No elucidation of molecular mechanisms that govern protection of neutrophils from serum-induced apoptosis
|Rafaghello L et al
|- Human BM-MSCs and neutrophils
- In vitro, MSC - conditioned media
- Delivery method: co-culture
- Effect of BM-MSCs on neutrophil survival and effector function.
|- Inhibition of apoptosis of resting and IL-8 activated neutrophils with both MSCs and MSC-conditioned media
- Recombinant IL-6 was found to protect neutrophils from apoptosis
- Effect was mediated by IL-6
|Lee JW et al
|- Human BM derived MSCs
- Ex-vivo perfused human lung
injured and intrabronchial
- Bacterial induction of acute
* IV or intrabronchial injection
|- Increased macrophage phagocytosis
- Reduced alveolar bacterial burden
- Intrabronchial KGF-7 caused: increased alveolar
macrophage phagocytosis and decreased bacterial load.
- KGF duplicated most of the antimicrobial effects of MSCs.
- In vitro: KGF-7 positive monocytes increased bacterial killing and monocyte survival and FGF-7 blocking antibodies
nullified antimicrobial effects ex vivo and in vitro.
Based on current clinical trials and irrespective of the treated disease condition or the mode of administration, MSC therapy appears relatively safe [3, 5]. Therapeutic applications of MSCs raise a series of concerns about the safety of culture-expanded MSCs for human use . However, further large scale clinical trials with rigorous reporting of adverse events are required to further define the safety profile of MSCs . Complications of MSC therapies include: (1) febrile reactions during or shortly after transfusion, (2) tumor modulation and malignant transformation, (3) increased risk of cancer, particularly hematologic malignancy, (4) genetic manipulation, induction of genetic instability and evolution of chromosomal abnormalities, (5) increased incidence of infectious complications, particularly in recipients of hematopoietic stem cell transplantation (HSCT) having graft versus host disease (GVHD) treated with MSCs, and (6) persistence of human
2. MSCs and sepsis
Sepsis is the leading cause of death in the intensive care units and it ranks among the top 10 causes of death in the general population worldwide. Despite the advances in medical care, mortality rates from sepsis remain as high as 30%-50% in severe cases . Sepsis is a systemic inflammatory response that is typically triggered by bacterial or other microbial infection and it involves a complex interaction between the microbial pathogen and the host immune system [11, 12]. The inflammatory response, designed to control infection, affects end-organ perfusion and exacerbates tissue injury leading to multi-organ failure . In the early phase of sepsis, endogenous proinflammatory cytokines and coagulation pathways become hyperactive and their adverse effects cause multi-organ failure, collapse of the circulatory system and ultimately death of the affected individual .
Sepsis is associated with a surge of systemic signaling molecules including cytokines and growth factors that may become uncontrollable . Stem cells have profound effects on the inflammatory response and coagulation cascade that are activated during sepsis . Stem cells have been shown to modulate more than 3000 genes in experimental sepsis models. They enhance the clearance of pathogens and repair of injured tissues in sepsis. In addition, stem cells have been found to have an impact on cell leak that is encountered during sepsis .
2.1. MSCs in sepsis and experimental sepsis models
Mesenchymal stroma is an essential component of tissue barriers and it participates in protecting the body from infections. A breach in the integrity of tissue barriers such as trauma can lead to translocation of bacteria and colonization of vital organs, thus ultimately leading to multiple organ failure and sepsis . Tissue injury compromises barrier function and increases the risk of infection and sepsis. Tissue injury can induce recruitment of MSCs from BM and promote their proliferation so as to reconstitute the integrity of injured tissues and mediate natural debridement . MSCs can modulate systemic response to bacterial infection and support tissue repair in addition to healing after being recruited at the sites of tissue injury . Sepsis is a devastating condition characterized by systemic activation of inflammatory and coagulation pathways in response to microbial invasion of sterile body organs or tissues . Severe sepsis, sepsis with at least one dysfunctional organ, is a leading cause of death in intensive care units (ICUs) as it is associated with mortality rates ranging between 30% and 50% .
The development of experimental sepsis models to elucidate the pathophysiology and progression of clinical sepsis spans over the last 8 decades. The following transitions in animal models took place since the 1930s: endotoxemia, bacteremia, ischemia and bowel perforation and finally cecal ligation puncture (CLP) and the colon ascends stent peritonitis (CASP) models . Genetic differences in mice and possibly humans are associated with differences in the inflammatory process initiated in response to sepsis and that ultimately affect the outcome of sepsis. Hence, transgenic animal models have been extensively utilized in sepsis research . Upon stimulation by endotoxins or proinflammatory mediators, activated neutrophils release a chromatin material composed of DNA and antimicrobial granular proteins in the form of neutrophil extra-cellular traps (NETs). The formation of NETs, NETOSIS, is an emerging field in sepsis research . However, the presence of NETOSIS is distinct from that of necrosis and apoptosis. NETOSIS can be experimentally induced by endotoxins such as lipopolysaccharides (LPS), Gram-negative as well as Gram-positive bacteria, fungi and proinflammatory cytokines such as activated platelets and interleukin-8 (IL-8). NET formation has been found to cause host tissue and cellular damage . LPS-induced endotoxemia in mice as well as plasma obtained from humans with severe sepsis were able to trigger NETOSIS. In vitro, NET formation resulted in endothelial cell damage while in vivo it caused hepatotoxicity in LPS-challenged mice . In septic hosts, NETs can exacerbate sepsis by releasing high concentrations of potent proteases, forming a chromatin meshwork and trapping host cells (erythrocytes, leukocytes and platelets) that can potentiate inflammation, coagulation and ischemia in involved tissues .
Microparticles are a heterogenous population of small membrane-coated vesicles that are released by several cell lines upon activation or apoptosis . Exosomes are a specialized category of microparticles with specific functions in immune response and protein sorting. Exosomes are released mainly from antigen presenting cells, although they have been identified after activation of platelets and mast cells and in body fluids such as urine or bronchoalveolar lavage . Although the role of exosomes in sepsis remains deeply unexplored, accumulating data suggest that microparticles and exosomes play a role in the three pathways clearly involved in the pathogenesis of sepsis: inflammation, thrombosis and vascular dysfunction .
Human MSCs possess antimicrobial and immunosuppressive effects that are partly mediated by the tryptophan catalyzing enzyme indoleamine-2, 3-dioxygenase (IDO) . Upon stimulation by inflammatory cytokines, MSCs exhibit broad spectrum antimicrobial effector functions directed against various clinically relevant pathogens and these effects are dependent on IDO and/or the antimicrobial peptide LL-37 . MSCs have antiapoptotic, antifibrotic and angiogenic properties. Interferon γ (IFN-γ) primes MSC-mediated immunoregulatory effects and induces nitrous oxide (NO) production in MSCs. NO exerts antiapoptotic effects on cardiomyocytes and has antiviral properties .
The role of microparticles and exosomes in mediating vascular dysfunction suggests that they may represent novel pathways in paracrine transcellular signaling in vascular microenvironment . Further studies may aid in the clarification of their exact effects in sepsis and the development of additional interventional strategies for the prevention and treatment of sepsis . Examples of experimental sepsis and infection models that utilized human as well as murine MSCs are shown in Tables 2 and 3 [19-35].
MSCs function at several levels of the inflammatory response, particularly in the early phase of sepsis, to regulate a wide panel of inflammatory cytokines and inhibit leukocyte infiltration into several target organs . In an endotoxemic rat model, human AT-MSCs had the following beneficial effects: (1) modulation of host responses, (2) reduction of inflammatory cytokine levels in serum and lung, (3) reduction of alveolar inflammatory cell infiltration in the lung, (4) reduction of liver injury, and (5) improvement of tissue hypoperfusion . As systemic administration of human-AT-MSCs at the onset of endotoxemia ameliorated the serological and histological signs of endotoxemia, they may become attractive candidates for cell therapy in the treatment of endotoxemia and septic shock .
Increasing evidence suggests that BM-MSCs secrete molecules that inhibit the effector function of immune cells . AT-MSCs are a recently discovered cell population with much in common to their BM-derived counterparts. Both BM-MSCs and AT-MSCs have been shown to be effective in certain pre-clinical studies as they effectively inhibit the activation of T-cells .
Cellular immunotherapy for septic shock (CISS) trial is the first trial of stem cell therapy in humans . It has 2 phases and the objectives of this Canadian trial are as follows: (1) in phase I, to establish safety and patient tolerability of stem cells and to find the optimal dose of stem cells to be administered, and (2) in phase II, to look at loose surrogates of efficacy for patients with septic shock . The study has two arms: (1) an observational arm, where patients do not receive stem cells, and (2) an interventional arm, where patients receive stem cells with three different dose schedules . The study is expected to address many aspects of stem cell therapy in patients having septic shock such as safety, tolerable dose and feasibility of use [13, 36].
In animal models of
2.2. Conclusions that can be drawn from experimental models
MSCs may be a potential new therapeutic modality in the prevention and reduction of sepsis-associated lung injury . Decreased systemic and pulmonary cytokine levels may prevent acute lung injury and organ dysfunction. Genetic effects downregulate inflammation-related genes such as IL-10 and IL-6 and upregulate genes involved in the promotion of phagocytosis and bacterial killing . The bacterial clearance effect could be party due to the upregulation of lipocalin -2 production by MSCs. However, lipocalin-2 antibodies have been found to block antimicrobial effects of MSCs .
In peritoneal sepsis models using murine MSCs; the following mechanisms were involved: down regulation of Th1 inflammatory responses, reduced inflammatory cytokines and chemokines as well as increased IL-10 level and induction of IL-10 T-regulatory cells . Apoptotic AT-MSCs represent an endogenous therapeutic strategy that may be enhanced for maximum clinical benefits . Treatment with apoptotic AT-MSCs caused attenuation of sepsis syndrome induced lung and kidney parenchymal injury through suppression of inflammation, apoptosis and oxidative stress and enhancement of anti-oxidation and anti-apoptosis in rodent models .
Human BM-MSCs possess direct antimicrobial activity that is mediated by secretion of human cathelicidin hCAP-18/IL-37 . Human MSCs participate in the innate response against Gram-negative bacteria through the secretion of the antimicrobial peptide IL-37 . MSCs inhibit apoptosis of both resting and activated neutrophils and they increase the viability of resting and activated neutrophils in various culture serum concentrations . MSCs can restore alveolar fluid clearance, reduce inflammation and exert antimicrobial activity party through keratinocyte growth factor (KGF) secretion . Lastly, cultured or banked human BM-MSCs may be effective in treating sepsis in high-risk patients .
3. MSCs and viral infections
Fetal membrane derived MSCs [FM-MSCs] are susceptible to
MSCs could express receptors that permit their infection by
Although pre-clinical studies have shown that MSC therapy can induce anti-inflammatory effects and enhance repair of the injured lung and despite the clinical and pathological similarities between acute lung injury and severe influenza infection, it was found that MSC therapy may not be effective for the prevention and/or treatment of acute severe influenza . It is well established that MSCs can be infected by
Several lines of evidence indicate that human BM-MSCs can maintain
4. MSCs and
Persisters are a small fraction of quiescent bacterial cells that survive lethal antibiotics or stresses but are capable of reactivation under certain circumstances. Despite the discovery of persisters more than 70 years ago, the mechanisms of persistence are still poorly understood . A number of pathways and genetic abnormalities have recently been identified and they may explain the mechanisms of persistence. These pathways include: DNA repair or protection, toxin-antitoxin modules, phosphate metabolism, antioxidative defense, efflux and macromolecule degradation . However, more sensitive techniques are required to have a better understanding of the mechanisms of persistence. Once the underlying mechanisms are elucidated, cellular therapies, vaccination and targeted treatments are likely to make significant improvements in the management of persistent infections .
Bacterial persistence is the hallmark of tuberculosis (TB). The remarkable success of
Studies have shown that (1)
4.1. The role of autologous MSC transplantation in the treatment of TB
Recently, autologous transplantation of MSCs has successfully been utilized in the treatment of infections caused by multi-drug resistant TB (MDR-TB) and even extensively drug resistant TB (XDR-TB) [57, 62, 63]. In one study, 27 patients in whom previous anti-TB drug therapy had been unsuccessful were included and they received autologous MSC transplantation . Positive clinical responses were obtained in all patients, bacterial discharge from lung was abolished in 20 patients and resolution of tissue damage and lung cavitation were achieved in 11 patients 4 months after MSC infusion . Also, persistent remission of the tuberculous process was obtained in 56% of patients who had follow-up for 2 years post MSC transplantation . In a second phase 1 clinical trial, 30 patients with MDR and XDR-TB received autologous MSC transplantation after 4 weeks of starting anti-TB therapy . Six months post-autologous MSC transplantation (1) no major adverse events were encountered and (2) 70% of patients showed radiological improvement, while 16.7% of patients showed stable radiological appearances . Eighteen months post-MSC transplantation, 53% of the patients were cured while 10% of transplanted patients had evidence of treatment failure . Therefore, combining standard anti-TB chemotherapy with autologous MSCT may become a promising maneuver to enhance the efficacy of treatment in patients with drug-resistant pulmonary TB [57, 62, 63].
5. MSCs and parasites
MSCs ameliorate liver injury and reduce fibrosis in mouse models of
5.1. MSCs in Chagas disease
Chagas disease is caused by infection with
The use of cell therapies to improve cardiac function has been attempted experimentally for more than two decades . The use of BM-derived cells to treat cardiac diseases gained impulse based on the observation that stromal BM cells could be induced to differentiate into cardiomyocytes in vitro and when transplanted into cryoinjured rat hearts improved myocardial function and promoted angiogenesis [72, 74, 75]. Another significant development was that hematopoietic stem cells (HSCs) obtained from transgenic mice expressing enhanced green fluorescent protein, when transplanted into infarcted hearts of syngenic mice, differentiated into cardiac muscle and vascular cells [72, 76]. Since then, many laboratories reported that HSCs and stromal cells derived from BM improved myocardial function in animal models of both cryoinjured and ischemic heart lesions . In one study, cardiac MSCs were isolated from hearts of green fluorescent protein transgenic mice then injected into left ventricular (LV) walls of mice chronically infected with
After the encouraging results in animal models, a clinical trial examining the feasibility and safety of intracoronary injection of autologous BM cell transplantation in patients with congestive cardiac failure due to chronic chagasic CMP was performed [72, 80]. Results of the trial showed that the procedure was safe and effective as cell therapy induced small but rather significant improvements in both ejection fraction and quality of life in patients included in the study [72, 80]. In an experimental cardiac ischemia model, the administration of granulocyte-colony stimulating factor (G-CSF) had beneficial effects on cardiac structure and function . Repeated administration of G-CSF in another experimental model of chronic chagasic CMP, which closely resembled human disease, induced beneficial effects on (1) cardiac structure as inflammation and fibrosis were reduced, and (2) cardiac function .
Based on the promising results of the previous safety trial, a larger multicenter, randomized, double-blinded and placebo-controlled trial was designed to test the efficacy of intra-coronary injection of BM-derived mononuclear cells (MNCs) in patients with chronic chagasic CMP [72, 82]. Although no serious adverse events were observed, this efficacy trial showed no additional benefit of intracoronary injection of BM- MNCs in chagasic patients with low ejection fraction, that is, intracoronary injection of BM-MNCs neither improved LV function nor improved quality of life in patient with chronic chagasic CMP [72, 82]. After the initial homing experiments, it was demonstrated that BM MNCs from non-chagasic syngeneic donors significantly reduced cardiac inflammation and fibrosis in mice with chronic
One of the most striking observations after cell therapy in mice, chronically infected with
It is expected that within a few years, scientists will be able to find the (1) best animal model, (2) appropriate stem cell dose, (3) appropriate stem cell type, (4) injection route, and (5) disease status that will result in benefits for chronic chagasic CMP patients . Despite the success of stem cell therapy in animals, preclinical models of Chagas disease have not translated into successful human studies . Addressing the challenges associated with future research and providing solutions to have acceptable levels of safety and strict quality controls would enable successful clinical applications of stem cell therapies in chagasic CMP .
Ultimately, transplantation of BM-derived cells may prove to be an important therapeutic modality in the treatment of end-stage chagasic heart disease . Identifying which cell type(s) is responsible for the effects observed in both animal studies and preliminary human experiments will be an important step in further improving this treatment . Since the percentage of stem cells (either hematopoeitic or mesenchymal) is minimal in the mononuclear fraction, use of purified stem cell population has the potential to significantly increase the therapeutic benefit of cell therapy in chagasic CMP .
6. MSCS and fungal infections
Despite the availability of new antifungal agents, mortality and morbidity related to invasive fungal infections is still high, particularly in patients with hematological malignancies and in recipients of SOT and HSCT [90, 91]. The recent advances in the immunopathogenesis of invasive aspergillosis have provided critical information to augment host immunity against fungal pathogens [90, 91]. Potential approaches for enhancement of the host immune system to combat invasive fungal infections include (1) administration of effector and regulatory cells such as granulocytes, antigen-specific T-cells, natural killer cells and dendritic cells, and (2) administration of cytokines, interferons and growth factors such as INF-γ, G-CSF and granulocyte monocyte-colony stimulating factor (GM-CSF) [90, 91]. Although promising results have been obtained from animal studies, limited data are available to draw conclusions on risks and benefits in clinical settings [90, 91]. So, appropriately designed, multicenter and international clinical trials are needed in order to improve the outcome of invasive fungal infections in immunocompromised individuals [90, 91]. MSC therapy in HSCT recipients has been found to facilitate faster control of invasive fungal infections .
Studies have shown that human cathelicidin LL-37 and its fragments LL13-37 and LL 17-37 exhibit similar potencies in inhibiting the growth of
7. MSCs and wound healing
Chronic non-healing wounds are a serious medical problem . Biofilms, which are bacterial communities attached to a surface and become protected by a polysaccharide coating, are believed to contribute significantly to the persistence of chronic wounds by altering the host immune response. Current treatment options are ineffective and do not significantly target biofilms . It has been shown that the paracrine factors secreted by reprogrammed MSCs accelerate wound healing and reduce bacterial growth in biofilm-infected wounds in mice . Therefore, clinical studies are needed to test the efficacy of these paracrine factors in the eradication of biofilms in patients with non-healing wounds .
In an in vitro study, MSCs have recently been shown to exert measurable antimicrobial activities in a synovial fluid setting, suggesting that they may have future application as adjunct therapy for peri-prosthetic joint infections . Also, AT-MSCs have been shown to enhance closure of enterocutaneous fistula and aided in the recovery and healing of wounds in a rat model .
8. MSCs and lung injury
Melatonin, the chief secretary product of the pineal gland, is an indirect antioxidant that acts to stabilize cell membranes thereby making them less susceptible to oxidative insults and ultimately suppressing inflammatory reactions . Combined melatonin and apoptotic AT-MSCs treatment has been found to be superior to either regimen alone in ameliorating lung injury in the setting of CLP-induced sepsis in a rodent model . Also, adult tissue-derived MSCs have been shown to have antimicrobial effects that inhibit bacterial growth in lung tissues .
BM-derived MSCs have unlimited potential clinical applications in acute lung injury, due to various pulmonary disorders and they exert their effects by various mechanisms .
Multipotent MSCs have shown remarkable therapeutic effects in preclinical models of both ARDS and sepsis . Initial research focused on the ability of MSCs to engraft at sites of tissue injury . Recent literature shows increasing evidence suggesting that MSCs exert their therapeutic effects through mechanisms that are unrelated to long-term incorporation into tissues of the host . One of the most compelling pathways is their capacity to interact with injured tissue through the release of soluble bioactive factors .
9. MSCs and neutrophils
MSCs participate in the regulation of inflammation and innate immunity by responding to pathogen-derived signals and by regulating the function of innate immune cells . MSCs derived from the BM and peripheral tissues share common basic cell-biological functions . MSCs contribute to the resolution of infection and inflammation by promoting the antimicrobial activity of polymorphonuclear leukocytes, a property that is exhibited by MSCs derived from either BM or peripheral glandular tissues . MSCs rescue neutrophils from nutrient- or serum-deprived cell death. Whether this effect is exerted through a specific signaling pathway or confining neutrophils in a resting state by MSCs requires further evaluation .
Both multipotent adult progenitor cells (MAPCs) and MSCs are adult stem cells that can be derived from BM and are currently utilized in tissue engineering due to their immunomodulatory and trophic effects . The use of stem-cell-based immunotherapy is very promising as in vitro studies have shown comparable suppressive effects of both human MSCs and human MAPCs . However, the broader expansion capacities of human MAPCs make them more attractive than human MSCs for clinical use . Neutrophils release many lysis-inducing factors and cause local tissue damage. Conversely, neutrophils themselves could become a target in controlling sepsis .
10. Antimicrobial effects of MSCs
Multipotent, BM-MSCs (MP-BM-MSCs) are culture-expanded, nonhematopoietic stromal cells with immunomodulatory properties that are currently being investigated as novel cellular therapies in the prevention and treatment of clinical diseases that are associated with immune dysfunction . Preclinical studies suggest that MP-BM-MSCs may protect against infectious challenge through direct or indirect pathways . Direct effects exerted by MP-BM-MSCs on the pathogen are manifested by reduction of pathogen burden by inhibition of growth through soluble factors and enhancement of antimicrobial function of immune cells . Indirect effects exerted by MP-BM-MSCs on the host include: (1) attenuation of proinflammatory cytokine and chemokine induction, (2) reduction of proinflammatory cells immigration into the sites of tissue injury or infection, and (3) reduction of immunoregulatory soluble and cellular factors that preserve organ function. These preclinical studies provide insights into the future therapeutic applications of MP-BM-MSCs .
Through toll-like receptor (TLR) signaling and immune crosstalk between MSCs and immune effector cells, MSCs become capable of maintaining a critical balance between (1) promotion of pathogen clearance during the initial phase of inflammatory response, and (2) suppression of inflammation to preserve host integrity and to facilitate tissue repair . The presumed or suggested roles of MP-BM-MSCs during infection can be divided into five phases as shown in Table 4 .
Human BM-MSCs have direct antimicrobial activity, against Gram-positive as well as Gram-negative bacteria, which is mediated in part through the secretion of human cathelicidin hCAP-LL-37 . Also, evidences suggest that MSCs position themselves between the acid fast bacilli harbored in the BM and the host protective T-cells. Hence MSCs can be a potential target for the treatment of latent TB . Targeting MSCs is not expected to lead to the evolution of new resistance in the pathogen as MSCs do not need to be directly targeted and as the host immune response needs to be manipulated . Upon stimulation of inflammatory cytokines, human MSCs exhibit broad-spectrum antimicrobial effector function directed against a range of clinically relevant bacteria, protozoal parasites and viruses . Human MSCs act as immunosuppressants that concurrently exhibit potent antimicrobial effector function thus encouraging further evaluation in clinical trials . Human multipotent MSCs exhibit broad-spectrum antimicrobial activity mediated by IDO .
|1||Detection of pathogens and damage signals||- Engagement of TLR-mediated signaling pathways
- Recruitment of MSCs at the sites of infection
|2||Activation of host immune response||- Maintenance of quiescent HSC pool
- BM emigration of activated HSCs
- Mobilization and emigration of immune effector cells from BM.
- Thymic development to augment response of immune effector cells
|3||Elimination of pathogens||- Production of microbiocidal soluble factors
- Containment of infectious pathogen within micro-environment (pathogen phagocytosis)
|4||Induction of proinflammatory gradients||- Antioxident soluble factor (HO-1)
- Antiinflammatory soluble factors such as: IDO, PGFZ, IL-10, TGF-B, TGF-6,
HLA-G5 and Galectin-1
|5||Modulation of proinflammatory host immune response||- Activation of function, differentiation and migration of immune effector cells.
- Augmentation of wound healing
- Enhancement of revascularization
- Inhibition of tissue toxicity
- Modulation of inflammation and organ dysfunction.
Human gut microbial communities reside in an open ecosystem subject to disruptions ranging from dietary change to toxin exposure and pathogen invasion . Host inflammatory mechanisms to remove harmful organisms and restrict bacteria to gut lumen commonly target conserved molecular patterns found on pathogens and commensals alike, yet healthy gut microbial communities can remain stable for years in humans . A delicate balance between microbial resilience and host tolerance thus allows for commensal persistence throughout a diverse range of perturbations while preventing commensal overgrowth or depletion, either of which could have deleterious effects on the host . Thus, antimicrobial peptide resistance mediates the resilience of prominent gut commensals during inflammation . Stem cell differentiation can be regulated by TLR activation. Activation of TLRs on MSCs increases osteogenesis and decreases adipogenesis . Upon exposure to microbial legends, stem cells change their differentiation to help the initial immune response . Microbial ligands can influence stem cell fate via pattern recognition receptors. Microbial ligands such as LPS and lipoproteins can alter: proliferation, differentiation, migration and the function of stem cells. In mice stem cell proliferation is stimulated by TLR activation, while in humans most TLR activity does not seem to affect stem cell proliferation . TLR activation alters stem cell differentiation, cytokine production of stem cells and immunosuppressive functions of MSCs . However, cytokine production can also be influenced by microenvironment, co-stimulatory molecules as well as downstream signaling pathways . The immunosuppressive function of MSCs can be stimulated or inhibited by TLR activation depending on the type of signaling pathways that are activated . With the identification of innate immune receptors on stem cells and the finding that microbial ligands can influence stem cell fate, a new era of stem cell research has begun .
11. MSCs and HSCT
Recent studies revealed that, during pathogen exposure, hematopoiesis may yield progeny in magnitudes that are different from those produced under routine or stable hemostatic circumstances . HSCs not only sustain blood cell formation following bleeding, BM damage or chemotherapeutic ablation, but also respond directly to microbial products as well as inflammatory cytokines thus permitting real-time alterations in the direction of hematopoiesis in response to exposure to a certain burden of pathogenic organisms .
Various evidences from experimental models and clinical studies suggest the implication of bacterial and fungal infections in the pathogenesis of acute GVHD . Appropriate treatment or prophylaxis of bacterial infections during the early post-HSCT period might be beneficial in reducing not only infection-related but also GVHD-related mortality . To eliminate the systemic proinflammatory cytokine surge induced by bacterial infection, the following are needed: (1) specific antimicrobial strategies, (2) therapies targeting the pathways of innate immunity, and (3) nutritional interventions that might help in reducing the risk of acute GVHD. These issues should be evaluated prospectively in clinical trials. In a retrospective cohort study that evaluated the risk factors for pneumonia-related death following HSCT and that included 691 patients, meta-analysis showed that the following were the risk factors that contributed to death: (1) acute GVHD grades II - IV, (2) CMV infection, and (3) receiving MSCs. Additionally, bacteremia and mold infections contributed to pneumonia-related deaths .
MSC therapy in HSCT recipients has been found to have the following advantages: (1) prevention and treatment of GVHD, (2) immune reconstitution, (3) induction of faster engraftment, (4) healing of infections and inflammatory disorders, and (5) reduction in the incidence of various infectious complications [92, 103, 104, 114, 115]. Studies have shown that administration of human BM-derived MSCs given during allogeneic bone marrow transplantation or human umbilical cord blood-derived MSCs in the post-transplant period, in patients with bone marrow failure, is safe and advantageous [92, 114]. In recipients of unrelated allogeneic HSCT following non-myeloablative conditioning therapy, co-infusion of MSCs did not show any pulmonary deterioration for up to 1 year post–transplant . Additionally, in recipients of haploidentical HSCT, infusion of umbilical cord–derived MSCs did not increase the incidence of pulmonary infections .
12. Nanotechnology in stem cell research and therapy
Stem cell tracking using modern imaging modalities offers new insights into understanding the biology and achieving the full therapeutic potentials of stem cell therapies . Currently used standard methods for tracking stem cells in vivo include: (1) MRI, (2) bioluminescence imaging, (3) positron emission tomography, (4) fluorescence imaging, (5) single-photon emission tomography, (6) X-ray computed microtomography, (7) Raman or surface enhanced Raman spectroscopy-based imaging, and (8) photoacoustic imaging [117-119]. The selection of the imaging modality and stem cell tracer or label should take into consideration: the clinical condition of the patient, the primary disease and the comorbid medical conditions .
Nanotechnology offers valuable information on migration, homing, survival, differentiation, function and the engraftment of transplanted stem cells [117, 121, 122]. The delivery of nanomaterials enables a personalized approach and individualized tailoring of nanotechnology and materials used to the specific needs of each patient . To be of most use, tracking methods should ideally be non-invasive, high resolution and allow tracking in three dimensions . To identify transplanted stem cells from the host tissue, optically active probes are usually used to label stem cells before their administration . Nanofibers have recently gained substantial interest for their potential application in tissue engineering . Nanofibers accommodate: (1) the survival and proliferation of human MSCs, and (2) the continuous differentiation of human MSCs into obsteoblasts and chondrocytes .
13. Homing and migration of MSCs
An important property of MSCs is their capacity for migration and homing in or around the zones damaged by trauma, inflammation, ischemia or tumor infiltration . Intravenous administration of MSCs causes their migration, in substantial numbers, into areas of tissue damage . Therefore, it is essential to understand the mechanisms involved in the homing and migration of MSCs. In addition, MSCs derived from various sources express different patterns of chemokines and their receptors . Hence, the possibility to modulate the migration ability of MSCs opens a new era for the development of directed migration of greater numbers of MSCs injected intravenously into the sites of injury .
14. Banking of MSCs
MSCs hold great potential for developing effective cellular therapies and current trends indicate that their clinical applications will continue to rise markedly . There has been considerable success in manufacturing and cryopreserving MSCs at laboratory level, but these successes have not translated into technologies developed at industrial scale . The development of cost-effective and advanced technologies for the production and cryopreservation of MSCs is a crucial step in the process of successful clinical cell therapy . Also, it is essential to have simple and appropriate but validated protocols for cell and tissue processing under good manufacturing conditions in order to develop a cost-effective banking of MSCs such as those obtained from umbilical cord blood .
15. Conclusions and future directions
MSCs are heterogeneous progenitor cells that have the capacity of self-renewal and multi-lineage differentiation. Their distinguished immunomodulation and immunosuppressive properties allowed MSCs to have several therapeutic applications. MSCs are essential constituents of the framework that supports organ integrity and tissue barriers. Suppression of both T and B cells enables them to be major players in controlling inflammatory response and in the innate response to bacterial infection. Human BM-MSCs possess direct antibacterial activity against Gram-negative bacilli and they have been shown to improve survival and reduce mortality in animal models having septic complications. Also, human BM-MSCs can act as drug delivery vehicles, enhance the effectiveness of conventional antimicrobials and may prevent the evolution of drug–resistant microbes. MSCs contain a subset of IL-17+ that is capable of inhibiting the growth of
Taking into consideration the remarkable success in the utilization of MSCs in the treatment of various infections in animal models and the few published clinical trials in humans with MDR infections, such as those caused by
Wong RSY. Mesenchymal stem cells: angels or demons. J Biomed Biotechnol. 2011; 2011: 459510; 1–8.
Ra JC, Shin IS, Kim SH, Kang SK, Kang BC, Lee HY, et al. Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans. Stem Cells Dev. 2011; 20 (8) 1297–1308.
Herberts CA, Kwa MS, Hermsen HP. Risk factors in the development of stem cell therapy. J Transl Med. 2011; 9 (29): 1–14.
Wang Y, Han Z-b, Song Y-p, Han ZC. Safety of mesenchymal stem cells for clinical application. Stem Cell Int. 2012; 2012: 652034; 1–4.
Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, et al. for the Canadian Trials Group. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and a meta-analysis of clinical trials. PLoS One 2012; 7 (10): e–47559.
Cornėlio DA, de Medeiros SRB. Genetic evaluation of mesenchymal stem cells. Rev Bras Hematol Hemoter. 2014; 36(4): 238–240.
von Bahr L, Sundberg B, Lönnies L, Sander B, Karbach H, Ljungman P, et al. Long-term complications, immuonological effects, and role of passage for outcome in mesenchymal stromal cell therapy. Biol Blood Marrow Transplant. 2012; 18 (4): 557–564.
Sundin M, Lindblom A, Orvell C, Barrett AJ, Sundberg B, Watz E, et al. Persistence of human parvovirus B19 in multipotent mesenchymal stromal cells expressing the erythrocyte P antigen: implications for transplantation. Biol Blood Marrow Transplant. 2008; 14 (10): 1172–1179.
Ning H, Yang F, Jiang M, Hu L, Feng K, Zhang J, et al. The correlation between cotransplantation of mesenchymal stem cells and higher recurrence rate in hematologic malignancy patients: outcome of a pilot clinical study. Leukemia. 2008; 22 (3): 593–599.
Leentjens J, Kox M, van der Hoven JG, Netea MG, Dickkers P. Immunotherapy for the adjunctive treatment of sepsis: from immunosuppression to immunomodulation, time for a paradigm change? Am J Respir Crit Care Med. 2013; 187 (12): 1287–1293.
Elman JS, Li M, Wang F, Gimble JM, Parekkadan B. A comparison of adipose and bone marrow-derived mesenchymal stromal cell secreted factors in the treatment of systemic inflammation. J Inflamm (Lond). 2014; 11(1):1.
Shin S, Kim Y, Jeong S, Hong S, Kim I, Lee W; et al. The therapeutic effect of human adult stem cells derived from adipose tissue in endotoxemic rat model. Int J Med Sci. 2013; 10 (1): 8–18.
Suen C, Cheung L. The world's first in-human stem cell trial for septic shock: a bench-to-bedside journey in critical care from the perspective of Dr Lauralyn McIntyre. UOJM 2013; 3: 8–10.
Gorbunov MV, Elliott TB, McDaniel DP, Lund K, Liao P-J, Zhai M, et al. Up-regulation of autophagy defence mechanisms in mouse mesenchymal stromal cells in response to ionizing irradiation followed by bacterial challenge. Edited by Yannik Bailly; In–Tech; 2013; ISBN: 978-953-51-1062-0.
Mai S, Khan M, Liaw P, Fox-Robichaud A, on behalf of the Canadadian Critical Care Translational Biology Group (CCCTBG). Experimental Sepsis Models. Edited by Luciano Azevedo; In–Tech; 2012. ISBN: 978-953-51-0780-4.
Azevedo LCP. Microparticles and exosomes: are they part of important pathways in sepsis pathophysiology? Severe sepsis and septic shock-understanding a serious killer. Edited by Dr Richardo Fernandez; In–Tech; 2012; ISBN: 978-953-307-950-9.
Meisel R, Heseler K, Nau J, Schmidt SK, Leinewever M, Pudelko S, et al. Cytomegalovirus infection impairs immunosuppressive and antimicrobial effector functions of human multipotent mesenchymal stromal cells. Mediators Inflamm. 2014; 2014: 898630.
Van Linthout S, Savvatis K, Miteva K, Peng T, Ringe J, Warstat K, et al. Mesenchymal stem cells improve murine acute CoxsackivirusB3-induced myocarditis. Eur Heart J. 2011; 32: 2168–2178.
Hall SR, Tsoyi K, Ith B, Padera RF Jr, Leaderer JA, Wang Z, et al. Mesenchymal stromal cells improve survival during sepsis in the absence of neutrophils. Stem Cells. 2013; 31 (2): 397-407.
Mei SHJ, Haitsma JJ, Dos Santos CC, Deng Y, Lai PFH, Slutsky AS, et al. Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care Med. 2010; 182 (8):1047–1057.
Luo C-J, Zhang F-j, Zhang L, Geng Y-q, Li Q-g, Hong Q, et al. Mesenchymal stem cells ameliorate sepsis-associated acute kidney injury in mice. Shock. 2014; 41 (2), 123–129.
Gupta N, Krasnodembskaya A, Kapetanaki M, Mouded M, Tan X, Serikov V, et al. Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia colipneumonia. Thorax 2012; 67 (6): 533–539.
Nemeth K, Leelahavanichkul A, Yuen PST, Mayer B, Parmelee A, Doi K, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E2- dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med. 2009; 15 (1): 42–49.
Gonzalez-Ray E, Gonzalez MA, Rico L, Buscher D, Delgado M. Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut 2009; 58 (7): 929–939.
Chang C-L, Leu S, Sung H-C, Zhen Y-Y, Cho C-L, Chen A, et al. Impact of apoptotic adipose-derived mesenchymal stem cells on attenuating organ damage and reducing mortality in rat sepsis syndrome induced by cecal puncture and ligation. J Transl Med. 2012; 10: 244.
Yang R, Liu Y, Kelk P, Qu C, Akiyama K, Chen C, et al. A subset of IL-17+ mesenchymal stem cells possesses anti- Candida albicanseffect. Cell Res 2013; 23 (1):107–121.
Sung P-H, Chang C-L, Tsai T-H, Chang L-T, Leu S, Chen Y-L, et al. Apoptotic adipose-derived mesenchymal stem cell therapy protects against lung and kidney injury in sepsis syndrome caused by cecal ligation puncture in rats. Stem Cell Res Ther. 2013; 4 (6): 155.
Meisel R, Brookers S, Heseler K, Degistirici Ö; Bülle H, Woite C, et al. Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2, 3-dioxygenase. Leukemia 2011; 25: 648–654.
Krasnodesmbskaya A, Song Y, Fang X, Gupta N, Serikov V, Lee J-W, et al. Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem Cells 2010; 28 (12): 2229–2238.
Krasnodesmbskaya A, Samarani G, Song Y, Zhuo H, Su X, Lee J-W, et al. Human mesenchymal stem cells reduce mortality and bacteremia in Gram-negative sepsis in mice in part by enhancing the phagocytic activity of blood monocytes. Am J Physiol Lung Cell Mol Physiol. 2012; 302 (10): L1003–L1013.
Kim ES, Chang YS, Choi SJ, Kim TK, Yoo HS, Ahn SY, et al. Intratracheal transplantation of human umbilical cord blood-derived mesenchymal stem cells attenuates Escherichia coli-induced acute lung injury in mice. Respir Res. 2011; 12 (108): 1-11.
Cassatella MA, Mosna F, Micheletti A, Lisi V, Tamassia N, Cont C, et al. Toll-like receptor-3-activated human mesenchymal stromal cells significantly prolong the survival and function of neutrophils. Stem Cells 2011; 29: 1001–1011.
Maqbool M, Vidyadaran S, George E, Ramasamy R. Human mesenchymal stem cells protect neutrophils from serum-deprived cell death. Cell Biol Int. 2011; 35: 1247–1251.
Raffaghello L, Bianchi G, Bertolotto M, Montecucco F, Busca A, Dallegri F, et al.. Human mesenchuymal stem cells inhibit neutrophil apoptosis: a model for neutrophil preseveation in the bone marrow niche. Stem Cells 2008; 26: 151–162.
Lee JW, Krasnodembskaya A, McKenna DH, Song Y, Abbott J, Matthay MA. Therapeutic effects of human mesenchymal stem cells in ex vivo human lungs injured with live bacteria. Am J Respir Crit Care Med. 2013; 187 (7): 751–760.
Kusadasi N, Groeneveld AB. A perspective on mesenchymal stromal cell transplantation in the treatment of sepsis. Shock 2013; 40 (5): 352–357.
Yuan Y, Lin S, Guo N, Zhao C, Shen S, Bu X, et al. Marrow mesenchymal stromal cells reduce methicillin-resistant Staphylococcus aureusinfection in rat models. Cytotherapy 2014; 16 (1): 56–63.
Kim H, Darwish I, Monroy M-F, Prockop DJ, Liles WC, Kain KC. Mesenchymal stromal (stem) cells suppress pro-inflammatory cytokine production but fail to improve survival in experimental Staphylococcaltoxic shock syndrome. BMC Immunol. 2014; 15:1.
Johnson V, Webb T, Dow S. Activated mesenchymal stem cells amplify antibiotic activity against chronic Staphylococcus aureusinfection (P2056). J Immunol. 2013; 190: 180, 11.
Dow S, Johnson V. Activated mesenchymal stem cells enhance antibiotic treatment of bacterial infections. Colorado State University Ventures, Inc. Posted by Sarah Belford on 14/11/2013; file No.: 12-060.
Weil BR, Herrmann JL, Abarbancell AM, Manukyan MC, Poynter JA, Meldrum DR. Intravenous infusion of mesenchymal stem cells is associated with improved myocardial function during endotoxemia. Shock 2011; 36 (3): 235–241.
Sisto F, Bonomi A, Cavicchini L, Cocce V, Scaltrito MM, Bondiolotti G, et al. Human mesenchymal stromal cells can uptake and release ciprofloxacin, acquiring in vitro anti-bacterial activity. Cytotherapy 2014; 16 (2): 181–190.
Todd GP, LeRoux MA, Danilkovitch-Miagkova A. Mesenchymal stem cells as vehicles for targeted therapies. Drug discovery and development-present and future. Edited by Dr Izet Kapetanovic; In–Tech; 2011. ISBN: 978-953-307-615-7.
Avanzi S, Leoni V, Rotola A, Alviano F, Solimando L, Lanzoni G, et al. Susceptibility of human placenta derived mesenchymal stromal/stem cells to human herpesviruses infection. PLoS One. 2013; 8 (8): e–71412.
Wei G, Lin M, Cai Z, Huang H. Cytomegalovirus infection in mesenchymal stem cells and their activation could be enhanced by nuclear factor-kB inhibitor pyrrolidindithiocarbamate in vitro. Transplant Proc. 2011; 43 (5): 1944–1949.
Smirnov SV, Harbacheuski R, Lewis-Antes A, Zhu H, Rameshwar P, Kotenko SV. Bone marrow-derived mesenchymal stem cells as a target for cytomegalovirus infection: implications for hematopoiesis, self-renewal and differentiation potential. Virology 2007; 360 (1): 6–16.
Cotter EJ, Maughan RT, Doran PP. Role of mesenchymal stem cells (MSC) in HIV-1 associated bone and lipid toxicities. Stem cells and cancer stem cells. Edited by M.A. Hayat; Springer; 2012; 8: 79–90.
Zhang Z, Fu J, Xu X, Wang S, Xu R, Zhao M. Safety and immunological responses to human mesenchymal stem cell therapy in difficult-to-treat HIV-1-infected patients. AIDS. 2013; 27 (8): 1283–1293.
Allam O, Samarani S, Ahmad A. Mesenchymal stem cell therapy in HIV-infected HAART-treated nonimmune responders restores immune competence. AIDS. 2013; 27 (8): 1349–1352.
Rodrigues ES, do Carmo Favarin M, de Macedo MD, Otaguiri KK, Orellana MD, Takayanagui OM. HTLV-1 infection in bone marrow mesenchymal stem cells isolated from HTLV-1 individuals. Retrovirology. 2014; 11 (Suppl l): P106.
Darwish I, Banner D, Mubareka S, Kim H, Besla R, Kelvin DJ, et al. Mesenchymal stromal (stem) cell therapy fails to improve outcomes in experimental severe influenza. PLoS One. 2013; 8: e–71761.
Zhao C, Wu N, Deng F, Zhang H, Wang N, Zhang W. Adenovirus-medicated gene transfer in mesenchymal stem cells can be significantly enhanced by the cationic polymer polybrene. PLoS One. 2014; 9 (3): e–92908.
Ma R, Xing Q, Shao L, Wang D, Hao Q, Li X. Hepatitis B virus infection and replication in human bone marrow mesenchymal stem cells. Virology J. 2011; 8 (486): 1–8.
Zhang Y. Persisters, persistent infections and Yin-Yang model. Emerg Microbes Infect. 2014; 3 (1): e–3.
Sikri K, Tyagi JS. The evolution of Mycobacterium tuberculosisdormacy models. Current Science. 2013; 105 (5): 607–616.
Raghuvanshi S, Sharma P, Singh S, Kaer LV, Das G. Mycobacterium tuberculosisevades host immunity by recruiting mesenchymal stem cells. Proc Natl Acad Sci U S A. 2010; 107 (50): 21653–21658.
Al-Anazi KA, Al-Jasser AM, Alsaleh K. Infections caused by Mycobacterium tuberculosisin recipients of hematopoietic stem cell transplantation. Front Oncol. 2014; 4: 231.
Kelly DM, ten Bokum AMC, O’Leary SM, O’Sullivan MP, Keane J. Bystander macrophage apoptosis after Mycobacterium tuberculosisH37 Ra infection. Infect Immun. 2008; 76 (1): 351–360.
Tousif S, Singh DK, Ahmad S, Moodley P, Bhattacharyya M, Van Kaer L, et al. Isoniazid induces apoptosis of activated CD4+ T cells: implications for post-therapy tuberculosis reactivation and reinfection. J Biol Chem. 2014; 289 (44): 30190–30195.
Das B, Kashino SS, Pulu I, Kalita D, Swamy V, Yeger H, et al. CD271+ bone marrow mesenchymal stem cells may provide a niche for dormant Mycobacterium tuberculosis. Sci Transl Med. 2013; 5 (170): 170 ra13.
Beamer G, Major S, Das B, Campos-Neto A. Bone marrow mesenchymal stem cells provide an antibiotic-protective niche for persistent viable Mycobacterium tuberculosisthat survive antibiotic treatment. Am J Pathol. 2014; 184 (12): 3170–3175.
Erokhin VV, Vasil’eva IA, Konopoliannikov AG, Chukanov VI, Tsyb AF, Bogdasarian TR. Systemic transplantation of autologous mesenchymal stem cells of the bone marrow in the treatment of patients with multidrug-resistant pulmonary tuberculosis. Probl Tuberk Bolezn Leak. 2008; 10: 3–6.
Skrahin A, Ahmed RK, Ferrata G, Rane L, Poiret T, Isaikina Y, et al. Autologous mesenchymal stromal cell infusion as part of adjunct treatment in patients with multidrug and extensively drug-resistant tuberculosis: an open-label phase 1 safety trial. Lancet Respir Med 2014; 2 (2): 108–122.
Thakur RS, Tousif S, Awasthi V, Sanyal A, Atul PK, Punia P, et al. Mesenchymal stem cells play an important role in host protective immune responses against malaria by modulating regulatory T cells. Eur J Immunol. 2013; 43: 2070–2077.
Sinha S, Medhi B, Sehgal R. Challenges of drug-resistant malaria. Parasite 2014; 21(61): 1-15.
Allahverdiyev A, Bagirova M, Elcicek S, Koc RC, Baydar SY, Findikli N, et al. Adipose tissue-derived mesenchymal stem cells as a new host cell in latent leishmaniasis. Am J Trop Med Hyg. 2011; 85 (3): 535–539.
Bodgan C, Donhauser N, Döring R, Röllinghoff M, Diefenbach A, Ritting MG. Fibroblasts as host cells in latent leishmaniasis. J Exp Med. 2000; 191 (12): 2121–2129.
Xu H, Qian H, Zhu W, Zhang X, Yan Y, Mao F. et al. Mesenchymal stem cells relieve fibrosis of Schistosoma japonicum-induced mouse liver injury. Exp Biol Med. 2012; 237 (5): 585–592.
Zhang Y, Mi JY, Rui YJ, Xu YL, Wang W. Stem cell therapy for the treatment of parasitic infections: is it far away? Parasitol Res. 2014; 113 (2): 607–612.
Abdul Aziz MT, Atta HM, Roshdy NK, Rashed LA, Sabry D, Hassouna AA, et al. Amelioration of murine Schistosoma mansoniinduced liver fibrosis by mesenchymal stem cells. J Stem Cell Reg Med. 2012; 8 (1): 28–34.
Spekker K, Leineweber M. Antimicrobial effects of murine mesenchymal stromal cells directed against Toxoplasma gondiiand Neospora caninum: role of immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs). Med Microbiol Immunol. 2013; 202 (3): 197–206.
de Carvalho AC, Carvalho AB, Mello DB, Goldenberg RC. Bone marrow-derived cell therapy in chagasic cardiac disease: a review of pre-clinical and clinical results. Cardiovasc Diagn Ther. 2012; 2 (3): 213–219.
Muratore CA, Baranchuk A. Current and emerging therapeutic options for the treatment of chronic chagasic cardiomyopathy. Vasc Health Risk Manag 2010; 6: 593–601.
Makino S, Fukuda K, Miyoshi S, Konishi F, Kodama H, Pan J, et al. Cardiomyocytes can be generated from bone marrow stromal cells in vitro. J Clin Invest. 1999; 103 (5): 697–705.
Tomita, S, Li R-K, Weisel RD, Mickle DA, Kim E-J, Sakai T, et al. Autologous transplantation of bone marrow cells improves damaged heart function. Circulation 1999; 100 (Suppl II): II-247–II-256.
Orlic D, Kajstura J, Chimenti S, Jakonluk I, Anderson SM, Li B, Plckel J, et al. Bone Marrow cells regenerate infarcted myocardium. Nature 2001; 410: 701–705.
Silva JD, Souza MC, Antunes MA, Xisto DG, Padua TN, Abreu TP, et al. Effects of bone marrow derived mesenchymal stromal cells on lung and distal organ damage in experimental malaria. Am J Respir Crit Care Med. 2014; 189(1): A5249.
Guarita-Souza LC, Carvalho KA, Woituwicz V, Rebelatto C, Senegaglia A, Hansen P, et al. Simultaneous autologous transplantation of cocultured mesenchymal stem cells and skeletal myoblasts improves ventricular function in a murine model of Chagas disease. Circulation 2006; 114 (Suppl I): I-120–I-124.
Larocca TF, de Freitas Souza BS, Silva CA, Kaneto CM, de Alcantara AC, Azevedo C-M, et al. Transplantation of adipose-derived stem cells in experimental chronic chagasic cardiopathy. Arq Bras Cardiol. 2013; 100 (5): 460–468.
Vilas-Boas F, Feitosa GS, Soares MB, Mota A, Pinho-Filho JA, Almeida AJ, et al. Early results of bone marrow cell transplantation to the myocardium of patients with heart failure due to Chagas disease. Arq Bras Cardiol. 2006; 87 (2): 1–7.
Macambira SG, Vasconcelos JF, Costa CR, Klein W, Lima RS, Guimaräes P, et al. Granulocyte colony-stimulating factor treatment in chronic Chagas disease: preservation and improvement of cardiac structure and function. FASEB J. 2009; 23 (11): 3843–3850.
Ribeiro Dos Santos RR, Rassi S, Feitosa G, Grecco OT, Rassi A Jr, da Cunha A, et al. Cell therapy in Chagas cardiomyopathy (Chagas arm of the multicenter randomized trial of cell therapy in cardiopathies study): a multicenter randomized trial. Circulation 2012; 125 (20): 2454–2461.
Soares MB, Lima RS, Rocha LL, Takyia CM, Pontes-de-Carvalho L, de Carvalho AC, et al. Transplanted bone marrow cells repair heart tissue and reduce myocarditis in chronic chagasic mice. Am J pathol. 2004; 164 (2): 441–447.
Goldenberg RC, Jelicks LA, Fortes FS, Weis LM, Rocha LL, Zhao D, et al. Bone marrow cell therapy ameliorates and reverses chagasic cardiomyopathy in a mouse model. J Infect Dis. 2008; 197 (4): 544–547.
Soares MB, Lima RS, Souza BS, Vasconcelos JF, Rocha LL, Dos Santos RR, et al. Reversion of gene expression alterations in hearts of mice with chronic chagasic cardiomyopathy after transplantation of bone marrow cells. Cell Cycle 2011; 10 (9): 1448–1455.
Teixeira AR, Gomes C, Nitz N, Sousa AO, Alves RM, Guimaro MC, et al. Trypanosoma cruziin the chicken model: chagas-like heart disease in the absence of parasitism. PLoS One Negl Trop Dis. 2011; 5 (3): e–1000.
Mukherjee S, Nagajyothi F, Mukhopadhyay A, Machado FS, Belbin TJ, , de Carvalho AC, et al. Alterations in myocardial gene expression associated with experimental Trypanosoma cruziinfection. Genomics 2008; 91: 423–432.
de Calvalho KA, Abdelwahid E, Ferreira RJ, Irioda AC, Guarita-Souza LC. Preclinical stem cell therapy in Chagas disease: perspectives for future research. World J Transpl. 2013; 3 (4): 119–126.
de Carvalho AC, Goldenberg RC, Jelicks LA, Soares MB, Dos Santos RR, Spray DC, et al. Cell therapy in Chagas disease. Interdiscip Perspect Infect Dis. 2009; 2009: 484358.
Lehrnbecher T, Kalkum M, Champer J, Tramsen L, Schmidt S, Klingebiel T. Immunotherapy in invasive fungal infection–focus on invasive aspergillosis. Curr Pharm Des. 2013; 19 (20): 3689–3712.
Lehrnbecher T, Tramsen L, Koehl U, Schmidt S, Bochennek K, Klingbiel T. Immunotherapy against invasive fungal diseases in stem cell transplant recipients. Immunol Invest. 2011; 40 (7-8): 839–852.
Özdoğul H, Yeral M, Boğa C, Kozanoğlu I. Use of mesenchymal cells to modulate immune suppression and immune reconstruction in a patient with aplastic anemia complicated by invasive sino-orbital aspergillosis. Turk J Hematol. 2014; 31: 181–183.
Wong JH, Ng TB, Legowska A, Rolka K, Hui M, Cho CH. Antifungal action of human cathelicidin fragment (LL13-37) on Candida albicans. Peptides 2011; 32 (10): 1996–2002.
Lathrop MJ, Brooks EM, Bonenfant NR, Sokocevic D, Borg ZD, Goodwin M, et al. Mesenchymal stromal cells mediate Aspergillushyphal extract-induced allergic airway inflammation by inhibition of the Th17 signaling pathway. Stem Cells Transl Med. 2014; 3: 194–205.
Smith AA, Bellows CF. The use of paracrine factors from reprogrammed mesenchymal stem cells to treat biofilm-infected wound in vivo. Basic Science, Clinical Congress. October 2013, Washington, DC.
Chen AF, Tuan RS. In vitro testing of adult mesenchymal stem cells as an adjunct therapy for treating periposthetic joint infections. Poster No. 0918. ORS 2012 Annual Meeting.
Volpe BB, Santos Duarte Ads, Ribeiro TB, Atocchero I, Kharmandayan P, Olalla Saad ST, et al. Mesenchymal stromal cells from adipose tissue attached to suture material enhance the closure of enterocutaneous fistulas in a rat model. Cytotherapy 2014; 16 (12): 1709–1719.
Chen H-H, Chang, C-L, Lin K-C, Sung P-S, Chaig H-T, Zhen Y-Y. Melatonin augments apoptotic adipose-derived mesenchymal stem cell treatment against sepsis-induced acute lung injury. Am J Transl Res. 2014; 6 (5): 439–458.
Xia P, Peng X. Study on MSCs transplantation in respiratory diseases. J Chem Pham Res. 2014; 6 (4): 447–449.
Chen X, Liang H, Lian J, Lu Y, Li X, Zhi S. The protective effect of bone marrow mesenchymal stem cell on lung injury induced by Vibrio vulnificussepsis. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2014; 26 (11): 821–826.
Pelosi P, Suthersan Y. Bone marrow-derived monocuclear cell therapy in sepsis-induced acute respiratory distress syndrome: different insults, different effects! Stem Cell Res Ther. 2013; 4 (143): 1–3.
Walter J, Ware LB, Matthay MA. Mesenchymal stem cells: mechanisms of potential therapeutic benefit in ARDS and sepsis. Lancet respir Med. 2014; 2 (12): 1016–1026.
Brandau S, Jakob M, Brukere KK, Bootz F, Giebel B, Radtke S. Mesenchymal stem cells augment the anti-bacterial activity of neutrophil granulocytes. PLoS One. 2014; 9 (9): e–106903.
Jacobs SA, Roobrouck VD, Verfaillie CM, Van Gool SV. Immunological characteristics of human mesenchymal stem cells and multipotent adult progenitor cells. Immunol Cell Biol. 2013; 91: 32–39.
Brown KA, Treacher DF. Neutrophils as potential therapeutic targets in sepsis. Discov Med. 2009; 6 (33): 118–122.
Auletta JJ, Deans RJ, Bartholomew AM. Emerging roles of multipotent, bone marrow-derived stromal cells in host defense. Blood 2012; 119 (8): 1801–1809.
Krasnodembskaya A, Song Y, Lee J-W, Matthay MA. Human mesenchymal stem cells exert antimicrobial activity in vitro and in vivo in part through the secretion of the antimicrobial peptide LL-37. Meeting Abstract: 183, 1: A 1246, 2011.
Rai RC, Battacharya D, Das G. Stem cells in infectious diseases. Insight and control of infectious disease in global scenario. Edited by Dr Roy Priti; In–Tech 2012; ISBN: 978-953-51-0319-6.
Cullen TW, Schofield WB, Barry NA, Putnam EF, Rundell EA, Trent MS, et al. Antimicrobial peptide resistance mediates resilience of prominent gut commensals during inflammation. Science 2015; 347: 170–175.
Bouwman LI. Microbial ligands alter the fate of stem cells. TLR activation influences survival, proliferation, differentiation and function of stem cells. Universiteit Ulrecht, 2009; 1–28.
Boika JR, Borghesi L. Hematopoiesis sculpted by pathogens: Toll-like receptors and inflammatory mediators directly activate stem cells. Cytokine. 2012; 57: 1–8.
Fuji S, Kapp M, Einsele H. Possible implications of bacterial infections in acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Front Oncol. 2014; 4 (89): 1–7.
Forslow U, Blennow O, Le Blanc K, Ringden, O, Gustafsson T, Mattson T, et al. Treatment with mesenchymal stromal cells is a risk factor for pneumonia-related death after allogeneic hematopoietic stem cell transplantation. Eur J Haematol. 2012; 89 (3): 220–227.
Si Y, Yang K, Qin M, Zhang C, Du Z, Zhang X, et al. Efficacy and safety of human umbilical cord derived mesenchymal stem cell therapy in children with severe aplastic anemia following allogeneic hematopoietic stem cell transplantation: a retrospective case series of 37 patients. Pediatr Hematol Oncol. 2014; 31(1): 39–49.
Moermans C, Lechanteur C, Boudoux E, Giet O, Henket M, Seidel L, et al. Impact of cotransplantation of mesenchymal stem cells on lung function after unrelated allogeneic hematopoietic stem cell transplantation following non-myeloablative conditioning. Transplantation 2014; 98 (3): 348–353.
Han DM, Wang ZD, Ding L, Zheng XL, Yan HM, Xue M. Effect of umbilical cord MSC infusion on the pulmonary infection in haploidentical hematopoietic stem cell transplantation. Zhongguo Shi Yan Xue Ye Xue Xa Zhi 2014; 22 (4): 1084–1088.
Gao Y, Cui Y, Chan JK, Xu C. Stem cell tracking with optically active nanoparticles. Am J Nucl Med Imaging. 2013; 3 (3): 232–246.
Li SC, Tachili LM, Luo J, Dethlefs DA, Chen Z, Loudon WG. A biological global positioning system: considerations for tracking stem cell behaviors in the whole body. Stem Cell Rev. 2010; 6 (2): 317–333.
Villa C, Erratico S, Razini P, Fiori F, Rustichelli F, Torrente Y, et al. Stem cell tracking by nanotechnologies. Int J Mol Sci. 2010; 11: 1070–1081.
Janowski M, Bulte JW, Walczak P. Personalized nanomedicine advancements for stem cell tracking. Adv Drug Deliv Rev. 2012; 64 (13): 1488-1507.
Edmundson M, Thanh NT, Song B. Nanoparticles based stem cell tracking in regenerative medicine. Theranostics 2013; 3 (8): 573–582.
Wang Y, Xu C, Ow H. Commercial nanoparticles for stem cell labelling and tracking. Theranostics 2013; 3 (8): 544–560.
Xin X, Hussain M, Mao JJ. Continuing differentiation of human mesenchymal stem cells and induced chondrogenic and osteogenic lineages in electrospun PLGA nanofiber scaffold. Biomaterials 2007; 28 (2): 316–325.
Kholodenko IV, Konieva AA, Kholodenko RV, Yarygin KN. Molecular mechanisms of migration and homing of intravenously transplanted mesenchymal stem cells. J Regen Med Tissue Eng 2013; 2 (4): 1–11.
Thirumala S, Goebel WS, Woods EJ. Manufacturing and banking of mesenchymal stem cells. Expert Opin Biol Ther. 2013; 13 (5): 673–691.
Cooper K, Viswanathan C. Establishment of a mesenchymal stem cell bank. Stem Cells Int. 2011; 2011: 905621.