Open access peer-reviewed chapter

The Rising Role of Mesenchymal Stem Cells in the Treatment of Various Infectious Complications

Written By

Khalid Ahmed Al-Anazi, Waleed K. Al-Anazi and Asma M. Al-Jasser

Submitted: November 26th, 2019 Reviewed: February 3rd, 2020 Published: March 10th, 2020

DOI: 10.5772/intechopen.91475

Chapter metrics overview

763 Chapter Downloads

View Full Metrics

Abstract

Mesenchymal stem cells are heterogenous adult multipotent stromal cells that can be isolated from various sources including: bone marrow, peripheral blood, umbilical cord blood, dental pulp, and adipose tissue. They have certain immunomodulatory, immunosuppressive, and antimicrobial properties that enable them to have several therapeutic and clinical applications including: treatment of autoimmune disorders, role in hematopoietic stem cell transplantation and regenerative medicine, as well as treatment of various infections and their associated complications such as septic shock and acute respiratory distress syndrome. Although more success has been achieved in preclinical trials on the use of mesenchymal stem cells in animal models than in human clinical trials, particularly in septic shock and Chagas disease, more progress has been made in both disorders after the recent use of specific sources and certain doses of mesenchymal stem cells. Nevertheless, the utilization of this type of stem cells has shown remarkable progress in the treatment of few infections such as tuberculosis. The clinical application of mesenchymal stem cells in the treatment of several diseases still faces real challenges that need to be resolved. The following book chapter will be an updated review on the role of mesenchymal stem cells in various infections and their complications.

Keywords

  • mesenchymal stem cells
  • host immunity
  • antimicrobial properties
  • septic shock
  • Mycobacterium tuberculosis
  • Chagas disease
  • human immunodeficiency virus

1. Introduction to mesenchymal stem cells

Mesenchymal stem cells (MSCs), which were first described by Alexander Fridenstein in the 1960s, are heterogeneous, non-hematopoietic, adult multipotent stromal progenitor cells that are capable of self-renewal as well as differentiation into multiple lineages and various cell types [1, 2, 3, 4, 5, 6, 7, 8]. They can be isolated from several sources including bone marrow (BM), peripheral blood (PB), umbilical cord blood (UCB), amniotic fluid, placenta, adipose tissue (AT), and dental pulp as shown in Table 1 [1, 2, 3, 4, 5, 6, 7, 8]. Although the BM is the main source of MSCs, these stromal cells constitute only a small fraction of the total number of cells populating the BM [2, 4, 5, 6].

1Bone marrow
2Peripheral blood
3Umbilical cord blood: Wharton’s jelly
4Placenta: chorionic villi of placenta
5Amniotic fluid
6Menstrual blood
7Fallopian tubes and cervical tissue
8Breast milk
9Adipose tissues: fat
10Dental pulp, periodontal ligaments, and exfoliated deciduous teeth
11Palatal tonsils
12Salivary glands
13Skeletal muscle tissues
14Dermal tissues
15Lung tissues and alveolar epithelium
16Liver tissues: fetal liver
17Synovial membrane and fluid
18Parathyroid glands

Table 1.

Sources of mesenchymal stem cells.

MSCs have the following distinguishing features: (1) ability to adhere to the plastic vessel under optimal culture conditions; (2) capability to differentiate into osteoblasts, adipocytes, and chondrocytes; and (3) having characteristic immunophenotypic profile on flow cytometry [1, 2, 3, 5, 6, 8, 9]. MSCs are characteristically positive for: CD 105, CD 73, and CD 90 and characteristically negative for the following surface markers: CD 45, CD 34, CD 11b, CD 14, CD 19, CD 79a, and HLA-DR. However, certain types of MSCs can occasionally show positivity or negativity for specific surface markers as shown in Table 2 [1, 2, 3, 5, 6, 8, 9, 10, 11, 12, 13, 14]. Also, MSCs can differentiate into other cell types including: myocytes, cardiomyocytes, and neurons [5].

PositiveNegative
Characteristic surface markersCD 105
CD 73
CD 90
CD 45
CD 34
CD 14
CD 11b
CD 19
CD 79a
HLA-DR
Other surface markers that may/may not be expressedCD 117
CD 166
CD 29
CD 44
CD 106
CD 9
CD 10
CD 13
CD 28
CD 33
CD 49b
CD 71
CD 164
CD 271
HLA-class I
Stro-1
SSEA-4
ITGA-11
CD 31
CD 33
CD 133

Table 2.

Surface markers of MSCs on Flow cytometry.

MSCs, mesenchymal stem cells; HLA, human leukocyte antigen.

The bold values are to differentiate characteristic from non-characteristic surface markers.

Several studies have shown that MSCs obtained from BM, AT, and other sources do express CD 34 surface markers [4, 15, 16, 17, 18]. MSCs can be seen in abundant numbers in the circulation under the following circumstances: stem cell mobilization with growth factors, tissue injuries, stroke, hypoxia, and inflammatory conditions [4, 19, 20, 21, 22, 23, 24]. Despite the efforts displayed over the last five decades including identification of nine transcriptional factors, little is known about the molecular basis underlying the stemness of MSCs and it is still unclear whether these recently discovered genes regulate stemness or only differentiation of MSCs [7].

Advertisement

2. Functions, properties, and therapeutic indications of MSCs

MSCs have immunomodulatory and immunosuppressive properties that enable them to have several therapeutic and clinical applications including: hematopoietic stem cell transplantation (HSCT), autoimmune disorders, regenerative medicine and tissue repair, neurological diseases, bone and cartilage disorders, as well as treatment of several infections and acute respiratory distress syndrome (ARDS). Details are shown in Table 3 [1, 2, 6, 8, 25, 26, 27, 28, 29]. MSCs are major constituents of the BM microenvironment and the HSC niche and apparently they are the masters of survival and clonality [30, 31, 32]. The main functions of MSCs include: formation of hematopoietic microenvironment, modulation of the activity of the immune system, and regulating cell trafficking [33].

  1. Hematopoietic stem cell transplantation:

    1. Enhancement of engraftment

    2. Prevention of graft versus host disease (GVHD)

    3. Treatment of GVHD

  2. Treatment of autoimmune diseases:

    1. Systemic lupus erythromatosus

    2. Rheumatoid arthritis

    3. Systemic sclerosis

    4. Type 1 diabetes mellitus

    5. Multiple sclerosis

    6. Crohn’s disease

  3. Regenerative medicine and tissue repair:

    1. Myocardial ischemia

    2. Cardiac dysfunction

    3. Chronic non-healing wounds

    4. Liver injury

    5. Myocardial infarction

    6. Dilated cardiomyopathy

    7. Critical limb ischemia

    8. Spinal cord injuries

  4. Treatment of various infections:

    1. Bacterial infections including sepsis and its associated acute respiratory distress syndrome

    2. Viral infections such as human immunodeficiency virus, hepatitis B and C viruses

    3. Parasitic infections such as Chagas disease, schistosomiasis, and malaria

    4. Mycobacterial infections such as tuberculosis

  5. Other indications:

    1. Macular degeneration, corneal reconstruction and transplantation

    2. Bones and joints: osteogenesis imperfecta, osteoarthritis, and osteoporosis

    3. Cancer gene therapy

    4. Amyotrophic lateral sclerosis

    5. Liver cirrhosis

Table 3.

Current and potential therapeutic indications for mesenchymal stem cells.

Advertisement

3. Role of MSCs in host defense and infections

The putative roles of BM-MSCs during infection are: (1) detection of pathogens, (2) activation of host immune responses, (3) elimination of pathogens, (4) induction of proinflammatory gradients, and (5) modulation of proinflammatory host immune response due to having specific immunoregulatory properties of MSCs including: inhibition of differentiation of monocytes to dendritic cells (DCs), alteration of cytokine profile of DCs, induction of tolerant phenotypes of naïve and effector T-cells, inhibition of antibody production by B-cells, and suppression of natural killer (NK) cell proliferation and NK-mediated cytotoxicity [1, 2, 28, 34]. BM-MSCs may augment antimicrobial responses, abridge proinflammatory and damage responses, and ameliorate associated tissue injury and they appear to function as a critical fulcrum providing balance by promoting pathogen clearance during the initial inflammatory response, and suppressing inflammation to preserve integrity of the host and facilitate tissue repair [1, 2, 34].

The immunomodulatory properties of MSCs are mediated by cell-to-cell interaction and the secreted cytokines [35, 36, 37]. MSCs could potentially be involved at multiple levels in host defense by mobilizing immune effector cells and modulation of proinflammatory immune responses to minimize tissue damage [1, 37]. BM-MSCs may protect against infectious challenge by direct effects on the pathogens or through indirect effects on the host [1]. However, placenta-derived MSCs and fetal membrane-derived MSCs are highly susceptible to herpes viruses including varicella zoster virus (VZV) [2, 38]. Several types of stem cells including BM-MSCs and neural stem cells can cross the blood brain barrier and reach not only brain tumors but also ischemic and injured tissues caused by certain infections in the brain and engraft there. Consequently, MSCs can be utilized as means of cellular carriers to deliver therapeutic agents to sites of brain injury in order to exert their therapeutic and tissue regenerative effects in the brain [39, 40, 41, 42, 43].

Advertisement

4. Antimicrobial properties of MSCs

MSCs have been shown to exhibit the following antimicrobial properties: (1) capacity to enhance antibacterial activity by interaction with the host innate immune system in order to increase antibiotic sensitivity, increase bacterial killing, and slow bacterial growth; (2) capacity to enhance bacterial clearance in preclinical models of sepsis, cystic fibrosis, and ARDS; and (3) secretion of antimicrobial peptides such as: interleukin (IL)-17, indoleamine 2,3-dioxygenase (IDO), β-defensins, lipocalin-2, and cathelicidin LL-37 [44, 45, 46]. Members of the chemokine family have been found to have antimicrobial peptide activity although the role of chemokines in immunity during infection is rather complicated [47].

Advertisement

5. MSCs in sepsis, ARDS, and chronic bacterial infections

5.1 MSCs in sepsis syndrome and septic shock

Sepsis syndrome and septic shock represent major health problems worldwide and they are leading causes of death in hospitalized patients due to their association with high rates of morbidity and mortality in the absence of effective therapy [48, 49, 50, 51]. Sepsis is a potentially lethal syndrome that can develop following an infection in which a breakdown in the immune homeostasis results in both proinflammatory and anti-inflammatory mechanisms that become uncoupled from normal regulation [50]. The inflammatory-driven maladaptive response induces disruption of endothelial and epithelial barriers, thus resulting in organ dysfunction. However, the host responds to sepsis by stimulating the proliferation of HSCs in the BM or by activating emergency hematopoiesis in an attempt to counteract the effects of sepsis on the function of multiple body organs [51]. Septic shock is a devastating complication of uncontrolled bacterial infection that carries a mortality rate of 20–50% [50, 52]. Currently, there is no specific treatment for septic shock and the management of this devastating complication of serious infections remains supportive. However, the following measures should be taken into consideration: early identification, fluid resuscitation, prompt institution of antibiotic therapy, control of the source of infection, circulatory support, and lung protection by mechanical ventilation [48, 49, 52, 53].

Based on numerous preclinical studies, cell-based therapies are potentially beneficial in the treatment of septic shock and ARDS. However, various types of stem cells including embryonic stem cells, MSCs, and induced pluripotent stem cells have been used in the treatment of sepsis and ARDS, but MSCs are the most commonly used stem cells in septic shock [53]. In patients with septic shock complicated by acute lung injury (ALI) and ARDS, the paracrine factors secreted by MSCs can: mediate endothelial and epithelial permeability, and increase alveolar fluid clearance in addition to other mechanisms that reduce the complications of septic shock [54].

In a mouse model of sepsis, lipopolysaccharide-preconditioned MSC transplantation has been shown to: ameliorate survival rate after transplantation, protect cells from apoptosis and organ damage, and have immunomodulatory therapeutic properties [55]. Also, transplanted MSC can secrete Toll-like receptor-4, which plays a seminal role in attenuating in vivo Escherichia coli-induced pneumonia and ALI through anti-inflammatory and antibacterial effects [56]. In experimental animal models of sepsis, the effectiveness of BM-MSCs was compared to that of Wharton’s jelly (WJ) of umbilical cord; both sources of MSCs regulated leukocyte trafficking and reduced organ dysfunction but only WJ-MSCs were able to improve bacterial clearance and survival [57]. In animal models of Staphylococcal toxic shock syndrome, MSCs; particularly AT derived MSCs; were able to suppress cytokine production and attenuate sepsis but they failed to improve survival [58, 59].

Several preclinical sepsis studies have suggested that MSCs are capable of: modulating inflammation, enhancing clearance of pathogens as well as tissue repair, thus resulting in improvement in symptoms and reduction in organ damage and finally improvement in survival and reduction in mortality rates [48, 49, 50, 52]. A meta-analysis that evaluated the preclinical use of MSCs in animal models of septic shock demonstrated that MSC treatment significantly reduced mortality rates and the results of this survey supported the decision to proceed to clinical trials that test the effectiveness of MSCs in treating infections causing sepsis in humans [60].

In a phase I clinical trial that included patients admitted to the intensive care unit (ICU) with septic shock, infusion of freshly cultured allogeneic BM-MSCs in doses up to 3 million cells/kg into these ICU patients was shown to be safe as this dose of stem cells did not exacerbate the elevated cytokine levels in the plasma of patients with septic shock [52, 61].

5.2 MSCs in ALI and ARDS

Bacterial pneumonia and sepsis from non-pulmonary causes are the most common etiologies of ALI and ARDS that are associated with mortality rates ranging between 25 and 50% [62, 63, 64, 65]. Management of ARDS is mainly supportive with: protective ventilation, fluid conservation, and antimicrobial therapy [62, 64]. In patients with bacterial pneumonia and sepsis, MSCs can attenuate inflammatory process and enhance bacterial clearance [63, 65]. MSCs secrete paracrine factors that can regulate lung permeability and decrease inflammation and this makes MSCs a potentially attractive therapeutic modality for ALI [62]. In patients with ARDS, MSCs can exert beneficial effects by secreting paracrine factors, microvesicles, and transfer of mitochondria. These secretory products have: (1) anti-inflammatory properties that participate in resolving injuries to lung endothelium and alveolar epithelium; (2) regulatory effects on alveolar fluid clearance, thus reducing lung edema; (3) antimicrobial effects mediated by release of antimicrobial factors; and (4) upregulation of monocyte/macrophage phagocytosis [66]. In Escherichia coli-injured human lungs, MSCs were able to: restore alveolar fluid clearance, reduce inflammation, and exert antimicrobial activity partly through secretion of keratinocyte growth factor [62].

In patients with bacterial pneumonia causing ALI and ARDS, MSCs could become a promising novel therapeutic modality and an ideal candidate for future cellular therapy due to the following reasons: (1) MSCs are able to differentiate into various cell types, (2) MSCs can secrete multiple bioactive molecules that are capable of stimulating recovery of injured cells and inhibiting inflammation, (3) MSCs lack immunogenicity, and (4) MSCs can perform immunomodulatory functions [62, 63, 65, 67]. In a phase I clinical trial, Jennifer Wilson et al. showed safety of allogeneic BM-MSCs administered to patients with ARDS [56, 68]. However, the role of MSCs in ARDS patients should be carefully evaluated by well-designed multicenter randomized clinical trials [68].

5.3 MSCs in severe and chronic infections

Chronic implant and wound infections that are characterized by biofilm formation are often difficult to treat and they usually require continuous antibiotic therapy for weeks to months. However, alternative therapies for chronically infected wounds include: use of antibiotic impregnated implant materials or biological scaffolds, administration of biofilm disrupting agents, and combining cellular immunotherapy with antibiotics [44].

In patients with very severe aplastic anemia (VSAA), prolonged neutropenia results in refractory and overwhelming bacterial infections as well as invasive fungal infections that are associated with significant morbidity and mortality in these severely immunocompromised individuals [69]. In patients with VSAA lacking human leukocyte antigen identical sibling donors and having refractory infections, co-transplantation of haploidentical HSCs and allogeneic BM-MSCs has been shown to be a safe and a promising therapeutic modality [69].

Studies have shown that: (1) secretion of cathelicidin LL-37 by MSCs could enhance bacterial products indicating that MSCs can upregulate antimicrobial activity in the presence of infection and (2) activated MSCs, when administered intravenously and in combination with conventional antibiotics, can potentially suppress and eradicate chronic Staphylococcus aureusbiofilm infection in difficult-to-treat locations. Thus, treatment with activated MSCs represents a novel therapeutic option for patients having highly drug-resistant infections [44].

5.4 MSCs in bone, joint, and dental infections

The multidirectional differentiation potential of BM-MSCs is essential for tissue repair after local injury of bones, joints, and medullary adipose tissue. Additionally, the regulation of multiple differentiation potentials of MSCs by various antimicrobial agents affects the recovery from bone and joint infectious diseases [70]. Minocycline induces the following favorable changes in MSCs: migratory capacity, proliferation, gene expression, and growth factor release, ultimately resulting in enhancement of angiogenesis. Also, the triple antimicrobial-loaded hydrogels reduce bacterial bioburden and preserve viability of MSCs in the presence of bacteria [71].

Gingival MSCs encapsulated in silver lactate-containing alginate hydrogel have successfully differentiated into osteogenic tissue and have shown promise for bone tissue engineering with antimicrobial properties against peri-implantitis caused by gram negative bacterial infections [72]. Synthesized antibiotic-containing scaffolds have been shown to possess significantly lower effects on proliferation and viability of human dental pulp stem cells when compared to the saturated ciprofloxacin/metronidazole solution [73].

Advertisement

6. MSCs in viral infections

Studies have shown that: (1) MSCs are susceptible to infection by members of the herpes group of viruses such as: cytomegalovirus, Epstein-Barr virus, herpes simplex virus (HSV) type 1, HSV-2, and VZV, and MSCs become functionally defective following infection with herpes viruses; (2) AT-MSCs can differentiate into functional hepatocyte-like cells but AT-MSCs undergoing hepatic differentiation are not susceptible to infection by hepatitis B virus in vitro; (3) human MSCs are permissive to the highly pathogenic avian influenza A/H5N1 infection and infection of MSCs can cause apoptosis and loss of their immunomodulatory activity; and (4) MSCs can significantly reduce the impairment of alveolar fluid clearance induced by influenza A/H5N1 infection in vitro and prevent or reduce influenza A/H5N1-associated ALI in vivo [28, 34, 74]. The extracellular vesicles (ECVs) secreted by MSCs have anti-inflammatory and anti-influenza properties. Hence, they can be used as cell-free therapy for influenza in humans [75]. Infection of MSCs by respiratory syncytial virus (RSV) alters their immunoregulatory functions by upregulating interferon (IFN)-β and IDO, thus accounting for the lack of protective RSV immunity and for the chronicity of RSV-associated lung diseases such as bronchial asthma and chronic obstructive airway disease [76]. In mice models, treatment with MSCs alleviates inflammation and mortality associated with Japanese encephalitis virus, which is a leading cause of viral encephalitis in Asia [77]. Zika virus infection of human MSCs promotes differential expression of proteins that are linked to several neurological disorders such as Alzheimer’s disease, Parkinson’s disease, autism, and amyotrophic lateral sclerosis [78].

MSCs exhibit immunomodulatory, anti-inflammatory, and pro-angiogenic properties, and therefore have the potential to improve the outcome of allogeneic HSCT in patients with AA. In a multicenter study that included 75 patients with AA, the combination of HSCs obtained from BM and PB sources as well as MSCs has resulted in amelioration of acute graft versus host disease (GVHD) and viremia resulting ultimately in an improved survival benefit [79].

6.1 MSCs in HIV infection and AIDS

Acquired immunodeficiency syndrome (AIDS), which is caused by human immunodeficiency virus (HIV), poses a real threat to human life [80]. Despite the advent of highly active antiretroviral therapy (HAART) that suppresses plasma viral load but does not cure disease, HIV-1 persists in latent tissue reservoirs, mainly in macrophages and T-helper lymphocytes, and this poses significant challenge to long-term cure [2, 80, 81, 82]. HIV-1 predominantly infects HSCs such as macrophages, monocytes, and T-helper lymphocytes [82]. Non-immune responders (NIRs) do respond to HAART, which effectively suppresses HIV replication, but do not show any improvement in their immune status as reflected by an increase in CD4+ T-cell counts [83]. More than 20% of HAART-treated HIV-infected individuals exhibit NIR phenotype and these individuals are at risk of opportunistic infections, cancer, and reduced life expectancy [83].

Coexposure to MSC-conditioned media can enhance the latency-reactivation efficacy of the approved latency reversing drugs vorinostat and panobinostat [81]. Undifferentiated AT resident MSCs are not permissive to HIV-1 infection despite that HIV-1 exposure may increase the expression of some hematopoietic lineage related genes [82]. It has been reported that transfusions of UCB-MSC or more specifically WJ are well tolerated and can efficiently improve immune reconstitution in HIV-infected individuals who are NIRs [83, 84]. Memory CD4 T cells are the key cells organizing all immune actions against HIV while being the targets of HIV infection [85]. MSCs can express receptors that permit their infection by HIV-1. Additionally, human T-lymphotropic virus (HTLV)-1 could infect and replicate in human BM-MSCs possibly by involvement or infiltration of CD4+ lymphocytes [2, 86, 87].

Advertisement

7. MSCs in parasitic infections

Recently, MSCs have been introduced to treat parasitic infections associated with tissue damage in the form of granuloma formation or organ fibrosis such as: schistosomiasis, malaria, and Chagas disease [88, 89]. Studies have shown that MSCs can: (1) ameliorate liver injury and hepatic fibrosis induced by Schistosoma japonicum, particularly when combined with conventional therapies such as praziquantel and (2) play an important role in improving host protective immune responses against malaria by modulating regulatory T cells [88, 89].

7.1 MSCs in Chagas disease

Chagas disease, which is caused by the protozoan Trypanosoma cruzi, is endemic in Central and Latin America. However, incidence of the disease has recently increased in the United States of America, Canada, Japan, Australia, and Europe due to migratory movements [2, 90, 91, 92, 93]. The disease has acute and chronic phases [90, 91, 92]. The acute phase is characterized by intense parasitemia with no or few symptoms while the chronic phase, which extends over indeterminate period of time that may span over years or decades, is characterized by the evolution of cardiac as well as gastrointestinal manifestations reflecting disease complications [90, 91]. Pathogenesis of chronic Chagas cardiomyopathy (CMP) is still debatable but the following have been proposed to be the main pathological mechanisms involved: parasite persistence, microcirculatory alterations, autoimmune mechanisms, and autonomic dysfunction [90, 94]. The cardiac complications of Chagas disease include: myocarditis, dilated CMP, heart failure, arrhythmias, heart block, thromboembolism, stroke, and sudden death [2, 90, 91, 94].

The available and future therapies of Chagas disease include: treatment of arrhythmias and heart failure, antiparasitic therapy, resynchronization treatment, heart transplantation, and stem cell therapies [2, 90, 91, 93, 95]. In patients with chronic Chagas CMP and cardiac failure, conventional pharmacologic therapies are limited by being not always effective, thus rendering the disease incurable [90, 91, 96]. Heart transplantation may occasionally be needed but the procedure has a number of problems including: shortage of donors, high costs, and complications of long-term immunosuppressive therapies administered to recipients of heart transplants [90, 95].

Different stem cell types and delivery approaches have been used in both preclinical models as well as clinical trials with the aim of improving cardiac function and reversing complications [95]. In animal models, stem cell therapies have shown reductions in: right ventricular dilatation, and inflammatory infiltrates as well as fibrosis [91, 93]. Stem cell therapy with BM-MSCs has emerged as a novel therapeutic option for Chagas CMP and heart failure [91, 93]. In a murine model of Chagas disease, cotransplantation of autologous BM-MSCs and skeletal myoblasts has been shown to be effective in reversing ventricular dysfunction [94]. Also, in an animal model of chronic Chagas disease, genetic modification of MSCs mobilized by granulocyte colony stimulating factor has increased the immunomodulatory actions and paracrine functions of MSCs by recruitment of suppressor cells such as regulatory T-cells and myeloid-derived suppressor cells [97].

Transplantation of MSCs has shown clinical efficacy in animal or mouse models but studies in humans have not shown equivalent success due to a number of challenges that need to be overcome [2, 91, 93, 95, 98]. In animal models of chronic Chagas CMP, cardiac MSCs have been shown to exert protective effects by decreasing the degrees of fibrosis and inflammatory infiltrates in the affected myocardium [99]. The beneficial effects of MSC therapy in Chagas mice models may be an indirect action of the cells on the heart rather than a direct action of the large numbers of transplanted MSCs on the myocardium [91, 96]. Tracking of infused BM-MSCs in animal models has shown migration of these cells to the heart and their participation in tissue repair or regeneration [91, 92, 93]. Although an early clinical trial of intracoronary injection of autologous BM-cells in patients with chronic Chagas CMP and heart failure showed safety and feasibility, a large multicenter, randomized double-blind, placebo-controlled trial using intracoronary infusion of BM-mononuclear cells showed no improvement in cardiac function or in quality of life in patients with chronic Chagas CMP [2, 99, 100].

Advertisement

8. MSCs in tuberculosis

Mycobacterium tuberculosis(MTB) remains a leading cause of morbidity and mortality due to infectious diseases in humans [101]. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB, mainly caused by non-adherence to antimicrobial therapy, are recognized health problems in: Eastern Europe, South Africa, and South East Asia [101, 102, 103]. Therapeutic strategies that are employed in the management of MDR/XDR TB include: directly observed treatment (DOTS), DOTS-Plus, recombinant human IL-2 by aerosol therapy, and recombinant IFN-γ [102].

Despite the strong host immune response in humans, MTB organisms are capable of persisting or staying dormant for prolonged periods of time, thus resulting in latent infection [104, 105, 106]. Hypoxia or hypoxemic microenvironment may favor dormancy of MTB and subsequent evolution of drug resistance [106]. MSCs play a crucial role in the ability of MTB to evade the potent host immune responses and cause TB. Hence, targeting MSCs or nitrous oxide (NO) seems a plausible therapeutic intervention for the design of new effective preventive strategies against TB [107]. Studies have shown that MSCs are recruited into the tuberculous granulomas and they position themselves between the harbored pathogen and the effector T-cells [107, 108, 109]. CD271+ BM-MSCs can provide an antimicrobial protective intracellular niche in the host in which dormant MTB can reside for prolonged periods of time [106, 109, 110, 111]. MTB infects and persists in a dormant form inside BM-MSCs even after successful antimicrobial therapy [112]. Virulent mycobacteria can manipulate Toll-like receptors and certain signaling pathways including nuclear factor kappa-light-chain-enhancer of activated B cells in order to survive inside the BM stem cells [112]. MSCs can increase NO production in Mycobacterium abscessus-infected macrophages through activation of tumor necrosis factor (TNF)-α in the presence of IFN-γ [113]. The cellular crosstalk between TNF-α and prostaglandin-E2 is essential for the increased production of NO in macrophages [113]. Consequently, MSCs may become an ideal choice as adjunct therapy in MDR and XDR TB particularly in individuals with comorbid medical conditions [102, 103, 114]. There are three main clinical trials on the use of MSCs in the treatment of MDR/XDR TB [115, 116, 117]. In the first trial, 27 patients with MDR/XDR TB who had been unsuccessfully treated with conventional anti-TB chemotherapy received autologous MSCs, the following results were obtained: all patients showed positive responses to MSC therapy, bacterial discharge from lungs was abolished in 20 patients, tissue damage and lung cavitation resolved in 11 patients, and persistent remission of TB was encountered in 56% of patients after 2 years of autologous MSC transplantation [115]. In the second study, a phase I clinical trial, 36 patients with MDR/XDR TB received anti-TB chemotherapy for 4 weeks; then, they were subjected to autologous MSC transplantation [116]. Six months after autologous transplantation of MSCs: no major adverse events were reported, 70% of patients showed radiological improvement, while 16.7% of patients showed stable radiological appearances. Eighteen months after autologous transplantation of MSCs: 53% of patients were cured, while 10% of patients showed evidence of treatment failure [116]. In the third study, a randomized clinical trial, 72 patients with MDR/XDR TB were included: 36 patients (control group) received conventional anti-TB chemotherapy only, and the other 36 patients (study group) received anti-TB chemotherapy and autologous MSC transplantation [117]. Successful outcomes were encountered in 81% of the study group and 40% of the control group. So, the addition of autologous MSC transplantation to conventional anti-TB chemotherapy significantly enhanced the response rates in patients with MDR/XDR TB [117]. Therefore, combining standard anti-TB chemotherapy with autologous MSC transplantation may ultimately become valuable in increasing the efficacy of anti-TB treatment in patients with MDR-TB [2, 102, 115, 116].

Advertisement

9. MSCs in fungal infections

Administration of human MSCs does not have negative impact on host response against Aspergillus fumigatus [118, 119]. Also, Aspergillus fumigatus does not stimulate MSCs to secrete cytokines that play a major role in the pathogenesis of GVHD indicating that Aspergillus fumigatus is not involved in the pathogenesis of GVHD following HSCT. In an animal model, infusion of BM-MSCs into mice infected with Paracoccidioides brasiliensis failed to induce any antimicrobial effects.

Advertisement

10. Conclusions and future directions

Since their first description in the 1960s, the history of MSCs has witnessed steady progress that ultimately resulted in their clinical application in the treatment of many disorders including several infectious diseases. Although the success has not been uniform with regard to various infections and despite the gap between the achievements in animal studies and results of clinical trials in humans, plenty of efforts have been made to resolve the remaining challenges in the clinical applications of MSCs in several diseases.

Some of the remaining challenges facing the utilization of MSCs in the clinical arena include: (1) encountering failure of treatment or resistance to therapy; (2) the need to have quality control and safety measures; (3) implementation of guidelines and design of specific protocols for: preparation and manufacture, banking and cryopreservation of MSC products, administration and therapeutic use of each type and source of MSCs, and finally tracing of infused MSCs; and (4) performing large prospective multicenter clinical trials on the use of specific MSCs in certain diseases in order to test their uniform efficacy and verify their long-term safety.

References

  1. 1. Auletta JJ, Deans RJ, Bartholomew AM. Emerging roles for multipotent, bone marrow-derived stromal cells in host defense. Blood. 2012;119(8):1801-1809. DOI: 10.1182/blood-2011-10-384354 [Epub: 6 January 2012]
  2. 2. Al-Anazi KA, Al-Jasser AM. Mesenchymal stem cells-their antimicrobial effects and their promising future role as novel therapies of infectious complications in high risk patients. In: Demirer T, editor. Progress in Stem Cell Transplantation. Rijeka: IntechOpen; 2015. DOI: 10.5772/60640
  3. 3. Abdal Dayem A, Lee SB, Kim K, Lim KM, Jeon TI, Seok J, et al. Production of mesenchymal stem cells through stem cell reprogramming. International Journal of Molecular Sciences. 2019;20(8):E1922. DOI: 10.3390/ijms20081922
  4. 4. Al-Anazi KA, Bakhit K, Al-Sagheir A, AlHashmi H, Abdulbaqi M, Al-Shibani Z, et al. Cure of insulin-dependent diabetes mellitus by an autologous hematopoietic stem cell transplantation performed to control multiple myeloma in a patient with chronic renal failure on regular hemodialysis. Journal of Stem Cell Biology and Transplantation. 2017;1(2):11. DOI: 10.21767/2575-7725.100011
  5. 5. Bobis S, Jarocha D, Majka M. Mesenchymal stem cells: Characteristics and clinical applications. Folia Histochemica et Cytobiologica. 2006;44(4):215-230
  6. 6. Kim N, Cho SG. Clinical applications of mesenchymal stem cells. Korean Journal of Internal Medicine. 2013;28(4):387-402. DOI: 10.3904/kjim.2013.28.4.387 [Epub: 1 July 2013]
  7. 7. Liu TM. Stemness of mesenchymal stem cells. Preliminary study. Journal of Stem Cell Therapy and Transplantation. 2017;1:071-073. DOI: 10.29328/journal.jsctt.1001008
  8. 8. Squillaro T, Peluso G, Galderisi U. Clinical trials with mesenchymal stem cells: An update. Cell Transplantation. 2016;25(5):829-848. DOI: 10.3727/096368915X689622 [Epub: 29 September 2015]
  9. 9. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, 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
  10. 10. Nauta AJ, Kruisselbrink AB, Lurvink E, Willemze R, Fibbe WE. Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells. Journal of Immunology. 2006;177(4):2080-2087. DOI: 10.4049/jimmunol.177.4.2080
  11. 11. Murray IR, Péault B. Q&A: Mesenchymal stem cells—Where do they come from and is it important? BMC Biology. 2015;13:99. DOI: 10.1186/s12915-015-0212-7
  12. 12. Wexler SA, Donaldson C, Denning-Kendall P, Rice C, Bradley B, Hows JM. Adult bone marrow is a rich source of human mesenchymal ‘stem’ cells but umbilical cord and mobilized adult blood are not. British Journal of Haematology. 2003;121(2):368-374. DOI: 10.1046/j.1365-2141.2003.04284.x
  13. 13. Lv FJ, Tuan RS, Cheung KM, Leung VY. Concise review: The surface markers and identity of human mesenchymal stem cells. Stem Cells. 2014;32(6):1408-1419. DOI: 10.1002/stem.1681
  14. 14. Kundrotas G. Surface markers distinguishing mesenchymal stem cells from fibroblasts. Acta Medica Lituanica. 2012;19(2):75-79. DOI: 10.6001/actamedica.v19i2.2313
  15. 15. Lin CS, Ning H, Lin G, Lue TF. Is CD34 truly a negative marker for mesenchymal stromal cells? Cytotherapy. 2012;14(10):1159-1163. DOI: 10.3109/14653249.2012.729817
  16. 16. Sidney LE, Branch MJ, Dunphy SE, Dua HS, Hopkinson A. Concise review: Evidence for CD34 as a common marker for diverse progenitors. Stem Cells. 2014;32(6):1380-1389. DOI: 10.1002/stem.1661
  17. 17. Stzepourginski I, Nigro G, Jacob JM, Dulauroy S, Sansonetti PJ, Eberl G, et al. CD34+ mesenchymal cells are a major component of the intestinal stem cells niche at homeostasis and after injury. Proceedings of the National Academy of Sciences of the United States of America. 2017;114(4):E506-E513. DOI: 10.1073/pnas.1620059114 [Epub: 10 January 2017]
  18. 18. Eto H, Ishimine H, Kinoshita K, Watanabe-Susaki K, Kato H, Doi K, et al. Characterization of human adipose tissue-resident hematopoietic cell populations reveals a novel macrophage subpopulation with CD34 expression and mesenchymal multipotency. Stem Cells and Development. 2013;22(6):985-997. DOI: 10.1089/scd.2012.0442 [Epub: 21 December 2012]
  19. 19. Alvarez P, Carrillo E, Vélez C, Hita-Contreras F, Martínez-Amat A, Rodríguez-Serrano F, et al. Regulatory systems in bone marrow for hematopoietic stem/progenitor cells mobilization and homing. BioMed Research International. 2013;2013:312656. DOI: 10.1155/2013/312656 [Epub: 17 June 2013]
  20. 20. Rochefort GY, Delorme B, Lopez A, Hérault O, Bonnet P, Charbord P, et al. Multipotential mesenchymal stem cells are mobilized into peripheral blood by hypoxia. Stem Cells. 2006;24(10):2202-2208 [Epub: 15 June 2006]
  21. 21. Lund TC, Tolar J, Orchard PJ. Granulocyte colony-stimulating factor mobilized CFU-F can be found in the peripheral blood but have limited expansion potential. Haematologica. 2008;93(6):908-912. DOI: 10.3324/haematol.12384 [Epub: 9 April 2008]
  22. 22. Gilevich IV, Fedorenko TV, Pashkova IA, Porkhanov VA, Chekhonin VP. Effects of growth factors on mobilization of mesenchymal stem cells. Bulletin of Experimental Biology and Medicine. 2017;162(5):684-686. DOI: 10.1007/s10517-017-3687-0 [Epub: 31 March 2017]
  23. 23. Xu L, Li G. Circulating mesenchymal stem cells and their clinical implications. Journal of Orthopaedic Translation. 2014;2(1):1-7. DOI: 10.1016/j.jot.2013.11.002
  24. 24. Koning JJ, Kooij G, de Vries HE, Nolte MA, Mebius RE. Mesenchymal stem cells are mobilized from the bone marrow during inflammation. Frontiers in Immunology. 2013;4:49. DOI: 10.3389/fimmu.2013.00049 [eCollection 2013]
  25. 25. Ding SSL, Subbiah SK, Khan MSA, Farhana A, Mok PL. Empowering mesenchymal stem cells for ocular degenerative disorders. International Journal of Molecular Sciences. 2019;20(7):E1784. DOI: 10.3390/ijms20071784
  26. 26. Mansoor H, Ong HS, Riau AK, Stanzel TP, Mehta JS, Yam GH. Current trends and future perspective of mesenchymal stem cells and exosomes in corneal diseases. International Journal of Molecular Sciences. 2019;20(12):E2853. DOI: 10.3390/ijms20122853
  27. 27. Leyendecker A Jr, Pinheiro CCG, Amano MT, Bueno DF. The use of human mesenchymal stem cells as therapeutic agents for the in vivo treatment of immune-related diseases: A systematic review. Frontiers in Immunology. 2018;9:2056. DOI: 10.3389/fimmu.2018.02056 [eCollection 2018]
  28. 28. Thanunchai M, Hongeng S, Thitithanyanont A. Mesenchymal stromal cells and viral infection. Stem Cells International. 2015;2015:860950. DOI: 10.1155/2015/860950 [Epub: 29 July 2015]
  29. 29. Yang K, Wang J, Wu M, Li M, Wang Y, Huang X. Mesenchymal stem cells detect and defend against gammaherpesvirus infection via the cGAS-STING pathway. Scientific Reports. 2015;5:7820. DOI: 10.1038/srep07820
  30. 30. Azadniv M, Myers JR, McMurray HR, Guo N, Rock P, Coppage ML, et al. Bone marrow mesenchymal stromal cells from acute myelogenous leukemia patients demonstrate adipogenic differentiation propensity with implications for leukemia cell support. Leukemia. 2019. DOI: 10.1038/s41375-019-0568-8 [Epub ahead of print]
  31. 31. Pinho S, Lacombe J, Hanoun M, Mizoguchi T, Bruns I, et al. PDGFRα and CD51 mark human nestin+ sphere-forming mesenchymal stem cells capable of hematopoietic progenitor cell expansion. The Journal of Experimental Medicine. 2013;210(7):1351-1367. DOI: 10.1084/jem.20122252 [Epub: 17 June 2013]
  32. 32. Pleyer L, Valent P, Greil R. Mesenchymal stem and progenitor cells in normal and dysplastic hematopoiesis-masters of survival and clonality? International Journal of Molecular Sciences. 2016;17(7):E1009. DOI: 10.3390/ijms17071009
  33. 33. Shi C. Recent progress toward understanding the physiological function of bone marrow mesenchymal stem cells. Immunology. 2012;136(2):133-138. DOI: 10.1111/j.1365-2567.2012.03567.x
  34. 34. Al-Anazi KA, Al-Anazi WK, Al-Jasser AM. The beneficial effects of varicella zoster virus. Journal of Hematology and Clinical Research. 2019;3:016-049. DOI: 10.29328/journal.jhcr.1001010
  35. 35. Kyurkchiev D, Bochev I, Ivanova-Todorova E, Mourdjeva M, Oreshkova T, Belemezova K, et al. Secretion of immunoregulatory cytokines by mesenchymal stem cells. World Journal of Stem Cells. 2014;6(5):552-570. DOI: 10.4252/wjsc.v6.i5.552
  36. 36. Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Andreini A, et al. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells. 2006;24(2):386-398. DOI: 10.1634/stemcells.2005-0008 [Epub: 25 August 2005]
  37. 37. Castro-Manrreza ME, Montesinos JJ. Immunoregulation by mesenchymal stem cells: Biological aspects and clinical applications. Journal of Immunological Research. 2015;2015:394917. DOI: 10.1155/2015/394917 [Epub: 19 April 2015]
  38. 38. 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):e71412. DOI: 10.1371/journal.pone.0071412. Print 2013
  39. 39. Abdi Z, Eskandary H, Nematollahi-Mahani SN. Effects of two types of human cells on outgrowth of human glioma in rats. Turkish Neurosurgery. 2018;28(1):19-28. DOI: 10.5137/1019-5149.JTN.18697-16.1
  40. 40. Dong HJ, Li G, Meng HP, Shang CZ, Luo Y, Wen G, et al. How can mesenchymal stem cells penetrate the blood brain barrier? Turkish Neurosurgery. 2018;28(6):1013-1014. DOI: 10.5137/1019-5149.JTN.22639-18.1
  41. 41. Conaty P, Sherman LS, Naaldijk Y, Ulrich H, Stolzing A, Rameshwar P. Methods of mesenchymal stem cell homing to the blood-brain barrier. Methods in Molecular Biology. 1842;2018:81-91. DOI: 10.1007/978-1-4939-8697-2_6
  42. 42. Liu L, Eckert MA, Riazifar H, Kang DK, Agalliu D, Zhao W. From blood to the brain: can systemically transplanted mesenchymal stem cells cross the blood-brain barrier? Stem Cells International. 2013;2013:435093. DOI: 10.1155/2013/435093 [Epub: 12 August 2013]
  43. 43. Christodoulou I, Goulielmaki M, Devetzi M, Panagiotidis M, Koliakos G, Zoumpourlis V. Mesenchymal stem cells in preclinical cancer cytotherapy: A systematic review. Stem Cell Research and Therapy. 2018;9(1):336. DOI: 10.1186/s13287-018-1078-8
  44. 44. Johnson V, Webb T, Norman A, Coy J, Kurihara J, Regan D, et al. Activated mesenchymal stem cells interact with antibiotics and host innate immune responses to control chronic bacterial infections. Scientific Reports. 2017;7(1):9575. DOI: 10.1038/s41598-017-08311-4
  45. 45. 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 [eCollection 2017]
  46. 46. Sutton MT, Fletcher D, Ghosh SK, Weinberg A, van Heeckeren R, Kaur S, et al. Antimicrobial properties of mesenchymal stem cells: therapeutic potential for cystic fibrosis infection, and treatment. Stem Cells International. 2016;2016:5303048. DOI: 10.1155/2016/5303048 [Epub: 26 January 2016]
  47. 47. Valdivia-Silva J, Medina-Tamayo J, Garcia-Zepeda EA. Chemokine-derived peptides: Novel antimicrobial and antineoplasic agents. International Journal of Molecular Sciences. 2015;16(6):12958-12985. DOI: 10.3390/ijms160612958
  48. 48. Laroye C, Gibot S, Reppel L, Bensoussan D. Concise review: Mesenchymal stromal/stem cells: A new treatment for sepsis and septic shock? Stem Cells. 2017;35(12):2331-2339. DOI: 10.1002/stem.2695 [Epub: 16 September 2017]
  49. 49. Laroye C, Lemarié J, Boufenzer A, Labroca P, Cunat L, Alauzet C, et al. Clinical-grade mesenchymal stem cells derived from umbilical cord improve septic shock in pigs. Intensive Care Medicine Experimental. 2018;6(1):24. DOI: 10.1186/s40635-018-0194-1
  50. 50. Johnson CL, Soeder Y, Dahlke MH. Concise review: Mesenchymal stromal cell-based approaches for the treatment of acute respiratory distress and sepsis syndromes. Stem Cells Translational Medicine. 2017;6(4):1141-1151. DOI: 10.1002/sctm.16-0415 [Epub: 9 January 2017]
  51. 51. Skirecki T, Mikaszewska-Sokolewicz M, Godlewska M, Dołęgowska B, Czubak J, Hoser G, et al. Mobilization of stem and progenitor cells in septic shock patients. Scientific Reports. 2019;9(1):3289. DOI: 10.1038/s41598-019-39772-4
  52. 52. McIntyre LA, Stewart DJ, Mei SHJ, Courtman D, Watpool I, Granton J, et al., Canadian Critical Care Trials Group; Canadian Critical Care Translational Biology Group. Cellular immunotherapy for septic shock. A phase I clinical trial. The American Journal of Respiratory and Critical Care Medicine. 2018;197(3):337-347. DOI: 10.1164/rccm.201705-1006OC
  53. 53. Guillamat-Prats R, Camprubí-Rimblas M, Bringué J, Tantinyà N, Artigas A. Cell therapy for the treatment of sepsis and acute respiratory distress syndrome. Annals of Translational Medicine. 2017;5(22):446. DOI: 10.21037/atm.2017.08.28
  54. 54. Li J, Huang S, Wu Y, Gu C, Gao D, Feng C, et al. Paracrine factors from mesenchymal stem cells: A proposed therapeutic tool for acute lung injury and acute respiratory distress syndrome. International Wound Journal. 2014;11(2):114-121. DOI: 10.1111/iwj.12202 [Epub: 26 December 2013]
  55. 55. Saeedi P, Halabian R, Fooladi AAI. Antimicrobial effects of mesenchymal stem cells primed by modified LPS on bacterial clearance in sepsis. Journal of Cellular Physiology. 2019;234(4):4970-4986. DOI: 10.1002/jcp.27298 [Epub: 14 September 2018]
  56. 56. Wilson JG, Liu KD, Zhuo H, Caballero L, McMillan M, Fang X, et al. Mesenchymal stem (stromal) cells for treatment of ARDS: A phase 1 clinical trial. The Lancet Respiratory Medicine. 2015;3(1):24-32. DOI: 10.1016/S2213-2600(14)70291-7 [Epub: 17 December 2014]
  57. 57. Laroye C, Boufenzer A, Jolly L, Cunat L, Alauzet C, Merlin JL, et al. Bone marrow vs Wharton's jelly mesenchymal stem cells in experimental sepsis: A comparative study. Stem Cell Research & Therapy. 2019;10(1):192. DOI: 10.1186/s13287-019-1295-9
  58. 58. Kim H, Darwish I, Monroy MF, Prockop DJ, Liles WC, Kain KC. Mesenchymal stromal (stem) cells suppress pro-inflammatory cytokine production but fail to improve survival in experimental staphylococcal toxic shock syndrome. BMC Immunology. 2014;15:1. DOI: 10.1186/1471-2172-15-1
  59. 59. Asano K, Yoshimura S, Nakane A. Adipose tissue-derived mesenchymal stem cells attenuate Staphylococcal enterotoxin A-induced toxic shock. Infection and Immunity. 2015;83(9):3490-3496. DOI: 10.1128/IAI.00730-15 [Epub: 22 June 2015]
  60. 60. Lalu MM, Sullivan KJ, Mei SH, Moher D, Straus A, Fergusson DA, et al. Evaluating mesenchymal stem cell therapy for sepsis with preclinical meta-analyses prior to initiating a first-in-human trial. eLife. 2016;5:e17850. DOI: 10.7554/eLife.17850
  61. 61. Schlosser K, Wang JP, Dos Santos C, Walley KR, Marshall J, Fergusson DA, et al., Canadian Critical Care Trials Group and the Canadian Critical Care Translational Biology Group. Effects of mesenchymal stem cell treatment on systemic cytokine levels in a phase 1 dose escalation safety trial of septic shock patients. Critical Care Medicine. 2019;47(7):918-925. DOI: 10.1097/CCM.0000000000003657
  62. 62. 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. The American Journal of Respiratory and Critical Care Medicine. 2013;187(7):751-760. DOI: 10.1164/rccm.201206-0990OC
  63. 63. Sung DK, Chang YS, Sung SI, Yoo HS, Ahn SY, Park WS. Antibacterial effect of mesenchymal stem cells againstEscherichia coliis mediated by secretion of beta- defensin- 2 via toll- like receptor 4 signalling. Cellular Microbiology. 2016;18(3):424-436. DOI: 10.1111/cmi.12522 [Epub: 27 October 2015]
  64. 64. Wang YY, Li XZ, Wang LB. Therapeutic implications of mesenchymal stem cells in acute lung injury/acute respiratory distress syndrome. Stem Cell Research & Therapy. 2013;4(3):45. DOI: 10.1186/scrt193
  65. 65. Morrison T, McAuley DF, Krasnodembskaya A. Mesenchymal stromal cells for treatment of the acute respiratory distress syndrome: The beginning of the story. Journal of the Intensive Care Society. 2015;16(4):320-329. DOI: 10.1177/1751143715586420 [Epub: 21 May 2015]
  66. 66. Laffey JG, Matthay MA. Fifty years of research in ARDS. Cell-based therapy for acute respiratory distress syndrome. Biology and potential therapeutic value. The American Journal of Respiratory and Critical Care Medicine. 2017;196(3):266-273. DOI: 10.1164/rccm.201701-0107CP
  67. 67. Hayes M, Curley G, Laffey JG. Mesenchymal stem cells - a promising therapy for acute respiratory distress syndrome. F1000 Medicine Reports. 2012;4:2. DOI: 10.3410/M4-2 [Epub: 3 January 2012]
  68. 68. Zhang GY, Liao T, Zhou SB, Fu XB, Li QF. Mesenchymal stem (stromal) cells for treatment of acute respiratory distress syndrome. The Lancet Respiratory Medicine. 2015;3(4):e11-e12. DOI: 10.1016/S2213-2600(15)00049-1
  69. 69. Yue C, Ding Y, Gao Y, Li L, Pang Y, Liu Z, et al. Cotransplantation of haploidentical hematopoietic stem cells and allogeneic bone marrow-derived mesenchymal stromal cells as a first-line treatment in very severe aplastic anemia patients with refractory infections. Europian Journal of Haematology. 2018;100(6):624-629. DOI: 10.1111/ejh.13060 [Epub: 25 April 2018]
  70. 70. Li H, Yue B. Effects of various antimicrobial agents on multi-directional differentiation potential of bone marrow-derived mesenchymal stem cells. World Journal of Stem Cells. 2019;11(6):322-336. DOI: 10.4252/wjsc.v11.i6.322
  71. 71. Guerra AD, Rose WE, Hematti P, Kao WJ. Minocycline enhances the mesenchymal stromal/stem cell pro-healing phenotype in triple antimicrobial-loaded hydrogels. Acta Biomaterialia. 2017;51:184-196. DOI: 10.1016/j.actbio.2017.01.021 [Epub: 7 January 2017]
  72. 72. Diniz IM, Chen C, Ansari S, Zadeh HH, Moshaverinia M, Chee D, et al. Gingival mesenchymal stem cell (GMSC) delivery system based on RGD-coupled alginate hydrogel with antimicrobial properties: A novel treatment modality for peri-implantitis. Journal of Prosthodontics. 2016;25(2):105-115. DOI: 10.1111/jopr.12316 [Epub: 27 July 2015]
  73. 73. Kamocki K, Nör JE, Bottino MC. Dental pulp stem cell responses to novel antibiotic-containing scaffolds for regenerative endodontics. International Endodontic Journal. 2015;48(12):1147-1156. DOI: 10.1111/iej.12414 [Epub: 24 December 2014]
  74. 74. Chan MC, Kuok DI, Leung CY, Hui KP, Valkenburg SA, Lau EH, et al. Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America. 2016;113(13):3621-3626. DOI: 10.1073/pnas.1601911113 [Epub: 14 March, 2016]
  75. 75. Khatri M, Richardson LA, Meulia T. Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model. Stem Cell Research & Therapy. 2018;9(1):17. DOI: 10.1186/s13287-018-0774-8
  76. 76. Cheung MB, Sampayo-Escobar V, Green R, Moore ML, Mohapatra S, Mohapatra SS. Respiratory syncytial virus-infected mesenchymal stem cells regulate immunity via interferon beta and indoleamine-2,3-dioxygenase. PLoS One. 2016;11(10):e0163709. DOI: 10.1371/journal.pone.0163709 [eCollection 2016]
  77. 77. Bian P, Ye C, Zheng X, Yang J, Ye W, Wang Y, et al. Mesenchymal stem cells alleviate Japanese encephalitis virus-induced neuroinflammation and mortality. Stem Cell Research & Therapy. 2017;8(1):38. DOI: 10.1186/s13287-017-0486-5
  78. 78. Beys-da-Silva WO, Rosa RL, Santi L, Berger M, Park SK, Campos AR, et al. Zika virus infection of human mesenchymal stem cells promotes differential expression of proteins linked to several neurological diseases. Molecular Neurobiology. 2019;56(7):4708-4717. DOI: 10.1007/s12035-018-1417-x [Epub: 30 October 2018]
  79. 79. Chen M, Zheng Z, Hu J, Yang T. Co-transplantation of mesenchymal stem cells can ameliorates acute GVHD and viremia after allo-HSCT for aplastic anemia: A multi-center retrospective study of 75 patients. HemaSphere. 2019;3:710. Poster Session II: Stem cell transplantation—Clinical. PS1537. DOI: 10.1097/01.HS9.0000564408.36600.07
  80. 80. Halder UC. Bone marrow stem cells to destroy circulating HIV: A hypothetical therapeutic strategy. Journal of Biological Research-Thessaloniki. 2018;25:3. DOI: 10.1186/s40709-018-0075-5 [eCollection: 29 December 2018]
  81. 81. Chandra PK, Gerlach SL, Wu C, Khurana N, Swientoniewski LT, Abdel-Mageed AB, et al. Mesenchymal stem cells are attracted to latent HIV-1-infected cells and enable virus reactivation via a non-canonical PI3K-NFκB signaling pathway. Scientific Reports. 2018;8:14702. DOI: 10.1038/s41598-018-32657-y
  82. 82. Nazari-Shafti TZ, Freisinger E, Roy U, Bulot CT, Senst C, Dupin CL, et al. Mesenchymal stem cell derived hematopoietic cells are permissive to HIV-1 infection. Retrovirology. 2011;8(1):3. DOI: 10.1186/1742-4690-8-3
  83. 83. 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. DOI: 10.1097/QAD.0b013e32836010f7
  84. 84. Zhang Z, Fu J, Xu X, Wang S, Xu R, Zhao M, et al. Safety and immunological responses to human mesenchymal stem cell therapy in difficult-to-treat HIV-1-infected patients. AIDS. 2013;27(8):1283-1293. DOI: 10.1097/QAD.0b013e32835fab77
  85. 85. Zhang J, Crumpacker C. Eradication of HIV and cure of AIDS, now and how? Frontiers in Immunology. 2013;4:337. DOI: 10.3389/fimmu.2013.00337
  86. 86. Cotter EJ, Chew N, Powderly WG, Doran PP. HIV type 1 alters mesenchymal stem cell differentiation potential and cell phenotype ex vivo. AIDS Research and Human Retroviruses. 2011;27(2):187-199. DOI: 10.1089/aid.2010.0114 [Epub: 7 October 2010]
  87. 87. Rodrigues ES, de Macedo MD, Pinto MT, Orellana MD, Rocha Junior MC, de Magalhães DA, et al. HTLV-1 infects human mesenchymal stromal cell in vitro and modifies their phenotypic characteristics. Virology. 2014;449:190-199. DOI: 10.1016/j.virol.2013.11.022 [Epub: 6 December 2013]
  88. 88. Zhang Y, Mi JY, Rui YJ, Xu YL, Wang W. Stem cell therapy for the treatment of parasitic infections: Is it far away? Parasitology Research. 2014;113(2):607-612. DOI: 10.1007/s00436-013-3689-4 [Epub: 26 November 2013]
  89. 89. 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. Experimental Biology and Medicine (Maywood, NJ). 2012;(5):237, 585-592. DOI: 10.1258/ebm.2012.011362
  90. 90. de Carvalho AC, Carvalho AB. Stem cell-based therapies in Chagasic cardiomyopathy. Biomed Research International. 2015;2015:436314. DOI: 10.1155/2015/436314 [Epub: 15 June 2015]
  91. 91. Jasmin, Jelicks LA, Koba W, Tanowitz HB, Mendez-Otero R, et al. Mesenchymal bone marrow cell therapy in a mouse model of chagas disease. Where do the cells go? PLoS Neglected Tropical Diseases. 2012;6(12):e1971. DOI: 10.1371/journal.pntd.0001971
  92. 92. Souza BS, Azevedo CM, d Lima RS, Kaneto CM, Vasconcelos JF, Guimarães ET, et al. Bone marrow cells migrate to the heart and skeletal muscle and participate in tissue repair afterTrypanosoma cruziinfection in mice. International Journal of Experimental Pathology. 2014;95(5):321-329. DOI: 10.1111/iep.12089 [Epub: 30 June 2014]
  93. 93. Irion CI, Paredes BD, Brasil GV, Cunha STD, Paula LF, Carvalho AR, et al. Bone marrow cell migration to the heart in a chimeric mouse model of acute Chagasic disease. Memórias do Instituto Oswaldo Cruz. 2017;112(8):551-560. DOI: 10.1590/0074-02760160526
  94. 94. Guarita-Souza LC, Carvalho KA, Woitowicz 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(1 Suppl):I120-I1124. DOI: 10.1161/CIRCULATIONAHA.105.000646
  95. 95. de Carvalho KA, Abdelwahid E, Ferreira RJ, Irioda AC, Guarita-Souza LC. Preclinical stem cell therapy in Chagas disease: Perspectives for future research. World Journal of Transplantation. 2013;3(4):119-126. DOI: 10.5500/wjt.v3.i4.119
  96. 96. Jasmin, Jelicks LA, Tanowitz HB, Peters VM, Mendez-Otero R, de Carvalho ACC, et al. Molecular imaging, biodistribution and efficacy of mesenchymal bone marrow cell therapy in a mouse model of Chagas disease. Microbes and Infection. 2014;16(11):923-935. DOI: 10.1016/j.micinf.2014.08.016 [Epub: 16 September 2014]
  97. 97. Silva DN, Souza BSF, Vasconcelos JF, Azevedo CM, Valim CXR, Paredes BD, et al. Granulocyte-colony stimulating factor-overexpressing mesenchymal stem cells exhibit enhanced immunomodulatory actions through the recruitment of suppressor cells in experimental Chagas disease cardiomyopathy. Frontiers in Immunology. 2018;9:1449. DOI: 10.3389/fimmu.2018.01449 [eCollection 2018]
  98. 98. Ribeiro Dos Santos R, Rassi S, Feitosa G, Grecco OT, Rassi A Jr, da Cunha AB, et al., Chagas Arm of the MiHeart Study Investigators. 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. DOI: 10.1161/CIRCULATIONAHA.111.067785 [Epub: 20 April 2012]
  99. 99. Silva DN, de Freitas Souza BS, Azevedo CM, Vasconcelos JF, Carvalho RH, Soares MB, et al. Intramyocardial transplantation of cardiac mesenchymal stem cells reduces myocarditis in a model of chronic Chagas disease cardiomyopathy. Stem Cell Research & Therapy. 2014;5(4):81. DOI: 10.1186/scrt470
  100. 100. 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. Arquivos Brasileiros de Cardiologia. 2006;87(2):159-166. DOI: 10.1590/s0066-782x2006001500014
  101. 101. Joshi L, Chelluri LK, Gaddam S. Mesenchymal stromal cell therapy in MDR/XDR tuberculosis: A concise review. Archivum Immunologiae et Therapiae Experimentalis. 2015;63(6):427-433. DOI: 10.1007/s00005-015-0347-9
  102. 102. Iyer RN, Chelluri EP, Chelluri LK. Role of mesenchymal stem cell based therapies in MDR/XDR TB and co-morbidities. Journal of Stem Cell Research & Therapy. 2015;5:284. DOI: 10.4172/2157-7633.1000284
  103. 103. Khan FN, Zaidi KU, Thawani V. Stem cell therapy: An adjunct in the treatment of mdr tuberculosis. Journal of Stem Cell Research & Therapeutics. 2017;3(3):259-261. DOI: 10.15406/jsrt.2017.03.00099
  104. 104. Sikri K, Tyagi JS. The evolution of Mycobacterium tuberculosis dormancy models. Current Science. 2013;105(5):607-616
  105. 105. Tornack J, Reece ST, Bauer WM, Vogelzang A, Bandermann S, Zedler U, et al. Human and mouse hematopoietic stem cells are a depot for dormant Mycobacterium tuberculosis. PLoS One. 2017;12(1):e0169119. DOI: 10.1371/journal.pone.0169119 [eCollection 2017]
  106. 106. Garhyan J, Bhuyan S, Pulu I, Kalita D, Das B, Bhatnagar R. Preclinical and clinical evidence of Mycobacterium tuberculosis persistence in the hypoxic niche of bone marrow mesenchymal stem cells after therapy. The American Journal of Pathology. 2015;185(7):1924-1934. DOI: 10.1016/j.ajpath.2015.03.028 [Epub: 8 June 2015]
  107. 107. Mittal R. Mesenchymal stem cells: the new players in the pathogenesis of tuberculosis. Journal of Microbial & Biochemical Technology. 2011;03(03). DOI: 10.4172/1948-5948.100000e3
  108. 108. Raghuvanshi S, Sharma P, Singh S, Van Kaer L, Das G. Mycobacterium tuberculosis evades host immunity by recruiting mesenchymal stem cells. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(50):21653-21658. DOI: 10.1073/pnas.1007967107 [Epub: 6 December 2010]
  109. 109. Al-Anazi KA, Al-Jasser AM, Alsaleh K. Infections caused by Mycobacterium tuberculosis in recipients of hematopoietic stem cell transplantation. Frontiers in Oncology. 2014;4:231. DOI: 10.3389/fonc.2014.00231 [eCollection 2014]
  110. 110. Das B, Kashino SS, Pulu I, Kalita D, Swami V, Yeger H, et al. CD271(+) bone marrow mesenchymal stem cells may provide a niche for dormantMycobacterium tuberculosis. Science Translational Medicine. 2013;5(170):170ra13. DOI: 10.1126/scitranslmed.3004912
  111. 111. Beamer G, Major S, Das B, Campos-Neto A. Bone marrow mesenchymal stem cells provide an antibiotic-protective niche for persistent viableMycobacterium tuberculosisthat survive antibiotic treatment. The American Journal of Pathology. 2014;184(12):3170-3175. DOI: 10.1016/j.ajpath.2014.08.024 [Epub: 16 October 2014]
  112. 112. Naik SK, Padhi A, Ganguli G, Sengupta S, Pati S, Das D, et al. Mouse bone marrow Sca-1+ CD44+ mesenchymal stem cells kill avirulent Mycobacteria but notMycobacterium tuberculosisthrough modulation of cathelicidin expression via the p38 mitogen-activated protein kinase-dependent pathway. Infection and Immunity. 2017;85(10). DOI: 10.1128/IAI.00471-17. Print October 2017. pii: e00471-17
  113. 113. Kim JS, Cha SH, Kim WS, Han SJ, Cha SB, Kim HM, et al. A novel therapeutic approach using mesenchymal stem cells to protect againstMycobacterium abscessus. Stem Cells. 2016;34(7):1957-1970. DOI: 10.1002/stem.2353 [Epub: 27 March 2016]
  114. 114. Arora VK, Dhot PS, Singhal P. Stem cells in MDR-TB and XDR-TB. Current Respiratory Medicine Reviews. 2014;10(4):238-240. DOI: 10.2174/1573398X11666150109223613
  115. 115. Erokhin VV, Vasil’eva IA, Konopliannikov AG, Chukanov VI, Tsyb AF, Bagdasarian TR, et al. Systemic transplantation of autologous mesenchymal stem cells of the bone marrow in the treatment of patients with multidrug-resistant pulmonary tuberculosis. Problemy Tuberkuleza i Boleznei Legkikh. 2008;10:3-6
  116. 116. Skrahin A, Ahmed RK, Ferrara G, Rane L, Poiret T, Isaikina Y, et al. Autologous mesenchymal stromal cell infusion as adjunct treatment in patients with multidrug and extensively drug-resistant tuberculosis: An open-label phase 1 safety trial. The Lancet Respiratory Medicine. 2014;2(2):108-122. DOI: 10.1016/S2213-2600(13)70234-0 [Epub: 9 January 2014]
  117. 117. Skrahin AE, Jenkins HE, Hurevich H, Solodovnokova V, Isaikina Y, Klimuk D, et al. Potential role of autologous mesenchymal stromal cells in the treatment of multidrug and extensively drug-resistant tuberculosis. European Respiratory Journal. 2016;48:PA1919. DOI: 10.1183/13993003.congress-2016.PA1919
  118. 118. Schmidt S, Tramsen L, Schneider A, Schubert R, Balan A, Degistirici Ö, et al. Impact of human mesenchymal stromal cells on antifungal host response againstAspergillus fumigatus. Oncotarget. 2017;8(56):95495-95503. DOI: 10.18632/ oncotarget.20753. [eCollection: 10 November 2017]
  119. 119. Arango JC, Puerta-Arias JD, Pino-Tamayo PA, Salazar-Peláez LM, Rojas M, González Á. Impaired anti-fibrotic effect of bone marrow-derived mesenchymal stem cell in a mouse model of pulmonary paracoccidioidomycosis. PLoS Neglected Tropical Diseases. 2017;11(10):e0006006. DOI: 10.1371/journal.pntd.0006006. [eCollection: October 2017]

Written By

Khalid Ahmed Al-Anazi, Waleed K. Al-Anazi and Asma M. Al-Jasser

Submitted: November 26th, 2019 Reviewed: February 3rd, 2020 Published: March 10th, 2020