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

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].

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].

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].