A Perspective on Mesenchymal Stromal Cell Transplantation in the Treatment of Sepsis
Kusadasi, Nuray*†; Groeneveld, A. B. Johan*
*Department of Intensive Care, Erasmus Medical Center, Rotterdam; and †Department of Intensive Care, Vlietland Hospital, Schiedam, the Netherlands
Received 23 Apr 2013; first review completed 16 May 2013; accepted in final form 7 Aug 2013
Address reprint requests to Nuray Kusadasi, MD, PhD, Department of Intensive Care Adults, Erasmus Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands. E-mail: email@example.com.
Co-correspondence: A. B. Johan Groeneveld, MD, PhD, FCCP, FCCM, Department of Intensive Care Adults, Erasmus Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands. E-mail: firstname.lastname@example.org.
The authors have no conflicts of interest or source of funding to declare.
ABSTRACT: Although a variety of disease-modifying agents have been studied as potential sepsis treatments, no beneficial effects on the course of sepsis, in terms of survival, have been observed until now. Because of their plasticity, mesenchymal stromal cells (MSCs) have been implicated as an effective novel therapy modality for various diseases and are widely used for cellular therapies and tissue engineering. The existing knowledge supports the idea that MSCs might be beneficial in sepsis treatment. Our objective was to selectively address the evidence, based on multistep processes, supporting the potential of MSC-based therapies in clinical sepsis trials. In this study, we performed a stepwise approach to defend the evaluation of MSC treatments for sepsis from the bench to the bedside. Altogether, the reviewed data postulate that the signals produced by inflamed tissues might determine the functional effects of MSCs. These effects include bacterial clearance, suppression of inflammation, antiapoptosis, or stimulation of regenerative responses. We conclude that the clinical application of MSCs is a feasible and well-tolerated approach and therefore may have benefits for patients with sepsis.
Appropriate antimicrobial drug administration and early adequate source control are the mainstays in the treatment of sepsis. Protocolized hemodynamic resuscitation, including goal-directed volume resuscitation and vasopressor support, and protective lung ventilation are the standards in the management of septic patients (1). No specific drugs have significantly ameliorated the septic process. In addition, although a variety of disease-modifying agents have been studied, none have demonstrated beneficial effects on the disease course in terms of survival, until now. The pathophysiology of sepsis is the result of a complex set of interactions between pathogens and the host immune system (2). Many studies underlie not only the failing of immune cell responses and cell-specific apoptosis, but also the endothelial and epithelial dysfunction in disease severity and the related multiple organ failure. The therapeutic and supportive alterations are exceedingly complex because of the interconnection between the multiple biological pathways involved in the septic process. The existing knowledge supports the idea that mesenchymal stromal cells (MSCs) might be beneficial in sepsis treatment. In studies involving in vivo animal models, these cells were capable of reducing mortality and organ dysfunction–related markers (3, 4). Notably, immunomodulation, antiapoptosis, increased bacterial clearance, and the protection from endothelial/epithelial cell dysfunction have been postulated as possible mechanisms of action describing how MSCs may improve septic outcomes. As the extrapolation from in vitro and animal studies is difficult, the clinical consequences of these properties on the potential treatment of sepsis remain unclear.
Our objective in this review article was to briefly address the evidence, based on multistep processes, supporting the potential of MSC-based therapies in sepsis clinical trials. Thus, we performed a structured analysis focusing on (a) the mechanistic causes of sepsis, (b) the predictability effect of MSCs based on proof-of-concept studies from animal and in vitro sepsis models, and (c) the safety, feasibility, and pharmacokinetic considerations of MSCs as treatments in other disease states. Altogether, we examined and evaluated the stepwise, bench-to-bedside evidence for MSCs as a potentially successful sepsis treatment.
GENERAL CHARACTERISTICS OF MSC
Mesenchymal stromal cells, which were first described by Friedenstein et al. (5) in 1966, comprise 0.001% to 0.01% of the bone marrow mononuclear cells and give rise to mesodermal cell derivates, including osteoblasts, adipocytes, chondrocytes, myoblasts, and, with varying degrees of reproducibility, ectodermal (neuronal cells) and endodermal cells (hepatocytes) (6). Because of their plasticity, MSCs from different tissue sources (e.g. fat, umbilical cord blood, and placental tissues) have been implicated as an effective and novel therapy modality for various diseases and are widely used for cellular therapies and tissue engineering. These modalities are dependent on the isolation of phenotypically defined MSC populations and on culture methodologies that generate and expand specific cells to replace or support the function of organs involved in diseases. A combination of approaches are used to purify MSCs. These approaches are based on physical and biological properties, such as plastic adherence, immunophenotyping, and in vitro multilineage differentiation potential (7).
Some remarkable features of MSCs include their ability to selectively migrate toward, engraft into, and exert positive functional effects on damaged tissue at injury sites—a process called homing. It has been hypothesized that MSC homing is similar to leukocyte homing, which consists of chemotaxis, adhesion, and extravasation into inflammation sites. In vitro studies have demonstrated the capacity of MSCs to migrate toward many cytokines, including stromal cell–derived factor 1, epidermal growth factor, platelet-derived growth factor, vascular endothelial growth factor, insulinlike growth factor, tumor necrosis factor α (TNF-α), and interleukin 1β (IL-1β) (8). In addition, in vivo MSC studies revealed the upregulation of the chemokine receptors CXCR4 and CCR7 in response to the injury-associated production of stromal cell–derived factor 1α (9). The exposure of MSCs to several factors, including Toll-like receptors (TLRs) and TNF-α, enhanced MSC chemoattraction by inducing the expression of chemokine receptors (8).
THE MSC-BASED THERAPY MECHANISMS OF ACTION IN SEPSIS
The potential mechanisms from MSC-based therapies in the prevention of widespread organ system dysfunction and sepsis are discussed in the following sections. A summary of the data described is schematically represented in Figures 1 and 2.
Induction of anti-inflammatory immune cell polarization
The interactions between pathogen-associated molecular patterns expressed on microbes and pathogen recognition receptors on antigen-presenting cells are involved in the initiation of the inflammatory response. In sepsis, patients surviving this initial hit might develop features of immunosuppression, which in turn can result in secondary infections and the organ function deterioration. This immunosuppressive state is caused, in part, by apoptotic immune cell loss and immune cell dysfunction, which is thought to occur by a chronically excessive proinflammatory state. From the latter point of view, MSCs might be beneficial in the treatment of sepsis by inducing anti-inflammatory immune cell polarization. The different functional effects of MSCs have been induced through TLR signaling in coculture conditions (10, 11). Toll-like receptor 3 priming was shown to induce anti-inflammatory MSCs, which produced indoleamine 2,3 dioxygenase, prostaglandin E2 (PGE2), IL-4, and IL-1R antagonists, while also decreasing transforming growth factor β induction. In contrast, TLR-4 priming induced proinflammatory MSCs, which produced IL-6, IL-8, and transforming growth factor β. Furthermore, TLR-3–primed MSCs suppressed T-cell activation, whereas TLR-4–primed MSCs augmented their activity. In vivo studies have shown that MSCs entrapped in the lung reduced inflammation by secreting TNF-α–stimulated gene/protein 6 (12). Regarding the adaptive immune system, MSCs were shown to directly inhibit T-cell functions, to induce a shift from a proinflammatory T-helper 1 phenotype (interferon γ and TNF-α production) to an anti-inflammatory T-helper 2 phenotype (IL-4, IL-5, IL-10, and IL-13 production), and to induce increased regulatory T-cell levels (13). The interaction between MSCs and immune cells, either by direct contact or by the indirect interaction with MSC-produced soluble factors, seems to induce anti-inflammatory immune cell phenotypes.
A harmful effect of excessive inflammation during sepsis and shock is the apoptotic death of immune, endothelial, and epithelial cells by activation of the caspase cascade, which has been widely observed during severe infections (14). The contribution of apoptosis in sepsis is supported by postmortem analysis of septic patients, which revealed extensive lymphocyte and gastrointestinal epithelial cell apoptosis. Specifically, gastrointestinal epithelial cell apoptosis might subsequently compromise the bowel wall barrier, resulting in the translocation of bacteria and/or endotoxins into the circulation. From this point of view, MSCs have been shown to functionally delay lymphocyte and neutrophil apoptosis through an IL-6–mediated mechanism that was associated with the downregulation of reactive oxygen species (15).
Improvement in endothelial/epithelial dysfunction
Increasing evidence supports the substantial role of endothelial and/or epithelial cell dysfunction in the deterioration of functional organ systems associated with the systemic inflammation observed during sepsis. A variety of soluble mediators, such as cytokines, chemokines, reactive oxygen species, proteases, and oxidases, are released by endothelial or immune cells and react with specific endothelial/epithelial cell receptors. These interactions lead to a widening of junctions, which is caused by the dissociation of tight junctional proteins and/or cytoskeletal contraction. Several studies revealed the importance of angiopoietins (ANGs) in these activation cascades (16). Angiopoietin 1 has been shown to enhance endothelial cell survival and barrier maintenance; however, in contrast, ANG-2 further activates endothelial cells and diminishes their barrier function by antagonizing the effect of ANG-1 by competitively binding to the tyrosine kinase receptor, Tie-2. Angiopoietin 1 is also involved in GTPase Rac activation and the generation of cortical actin fibers, which promotes cell spreading and decreases endothelial permeability. Sepsis-induced endothelial/epithelial injury is best evaluated in acute lung injury models. An ANG-1 cell–based intervention in experimental acute lung injury has shown treatment benefits. The use of MSCs that overexpressed ANG-1 prevented lung injury and inflammation as measured by morphological, biochemical, and molecular indices (17). Considering that MSCs can release ANG-1 and improve alveolar epithelial permeability, their use in sepsis may also be beneficial by improving endothelial permeability, at least in part by shifting the local lung milieu from ANG-2 to ANG-1. Moreover, MSCs have been shown to differentiate into epithelial and endothelial cells and engraft into damaged tissue, which indicates their possible role in histological recruitment and repair of the endothelial/epithelial layer (18, 19). The ability of mature endothelium/epithelium tissues to proliferate is limited, and increasing evidence indicates a role for the recruitment and/or proliferation of endothelial/epithelial progenitor cells is to reconstitute the endothelial/epithelial monolayer (20). Mesenchymal stromal cells have been shown to stimulate progenitor cell migration. Mesenchymal stromal cells were also demonstrated to aid in the regenerative response following lung injury, in part via the secretion of the cytoprotective agent keratinocyte growth factor, which resulted in restoration of endothelial/epithelial permeability and increased alveolar fluid clearance (21). Other authors demonstrated that IL-6 and TNF-α induce vascular endothelial growth factor production by MSCs through ERK-, JNK-, and PI3K-mediated mechanisms (22). The latter data indicate that a coculture strategy with these cytokines may enhance MSC-related injury repair. Altogether, these data suggest a role for the histological improvement of endothelial/epithelial dysfunction, either by stimulating the mobilization of progenitor cells or by the differentiation into endothelial/epithelial cells. From these functional points of view, MSCs may reduce endothelial/epithelial cell permeability by inducing cytoprotective agents and recruiting endothelial/epithelial progenitor cells.
EXPERIMENTAL SEPSIS STUDIES UTILIZING MSC-BASED THERAPIES
Systemic review and meta-analysis of preclinical models of sepsis showed that MSC therapy reduced early and late mortality and markers of organ dysfunction, modulated the inflammatory response, and increased pathogen clearance (3, 4). The cecal ligation and puncture and endotoxemia models have been utilized to evaluate the efficacy of MSC-based cell therapy in sepsis. Although these models have limitations, they reflect the physiology, immune response, and time course of postoperative sepsis in humans, thereby making them attractive experimental models. Xu and colleagues (23) were one of the first groups to demonstrate that MSC infusion in a murine endotoxemia model reduced serum levels of proinflammatory cytokines and decreased endotoxin-induced lung injury. Nemeth et al. (24) elegantly demonstrated the mechanisms of action provided by MSCs to ameliorate the inflammation cascade in cases of sepsis. These authors showed that lipopolysaccharide and TNF-α activated nuclear factor κB signaling during experimental sepsis. This action, in turn, induced the production of cyclooxygenase 2 and PGE2 by MSCs. Subsequently, this action induced PGE2-altered macrophage function by decreasing TNF-α and IL-6 production and increasing IL-10 levels. In that study, MSC treatment resulted in prolonged survival and improved organ function (e.g., kidney, liver, and pancreas). Those authors also suggested that a possible mechanism of MSC treatment is decreased neutrophil migration into tissues and the subsequent myeloperoxidase release from neutrophils, which results in diminished organ dysfunction. In addition, those authors and others have shown that MSCs were able to reduce bacterial burden by directly secreting antimicrobial peptides, including LL-37 (C-terminal part of cathelicidin, antimicrobial peptide), which directly retarded bacterial growth (25). Furthermore, improved cardiac function following MSC infusion has also been demonstrated (26).
CLINICAL STUDIES UTILIZING MSC-BASED THERAPIES
Currently, different sources of MSCs are being used in human clinical trials for a variety of diseases, including cancer, autoimmune disorders, inflammatory bowel disease, ischemic heart disease, graft-versus-host disease, single-organ transplantation strategies, severe hemorrhage, and acute kidney injury. Gholamrezanezhad and colleagues (27) reported the first biodistribution of MSCs in human cirrhosis by transplanting and tracking 111In-oxine radiolabeled MSCs by magnetic resonance imaging. They observed that after MSC peripheral vein infusion most of the cells were initially entrapped within the lung capillaries, but over the subsequent 48 h, a significant proportion of the cells migrated from the lungs to the liver and spleen. Those authors also showed that these cells could be visualized in vivo at least 10 days after the initial infusion. Given the current evidence, the clinical studies that have utilized MSC-based therapies demonstrate that MSC transplantation is safe and feasible in humans (systemic review, unpublished data). No adverse events have been observed in the postinfusion period following MSC administration, except in one study, in which creatinine levels were transiently increased in two patients 7 and 14 days after MSC infusion. Although a sustained curative effect has not been consistently obtained in the variety of clinical conditions MSC treatments have been used in, the number of studies showing a clear therapeutic benefit from MSCs is increasing, which emphasizes the potential efficacy for MSCs. Recently, Lalu and colleagues (28) published a meta-analysis of safety in MSC-based clinical trials. These authors provided a systematic examination for adverse events related to the use of MSCs and did not identify any significant safety signals other than transient fever. Their overall conclusion was that MSC treatment appears to be a safe therapy.
MSC THERAPY ASSOCIATED THEORETICAL RISKS
In a recent review, Herberts and colleagues (29) emphasized the potential risk of stimulation and growth of previously undetected tumors by MSCs when administering these cells to patients. However, in vitro and in vivo studies evaluating the effects of MSC administration on cancer cells reported conflicting data, which consisted of inhibition, enhancement, and no effect on tumor growth (30). These same authors emphasized that the relevance of these observations, with regard to clinical use in humans, is difficult to assess and that the likelihood of that type of risk is unknown. In parallel, no supporting evidence has been found for the transformation of human MSCs into cancer cells (31). Moreover, the differentiation of MSCs into inappropriate cell types, including adipocytes and osteocytes, has been described in a mouse infarcted-heart model (32). Another theoretical risk is the ectopic grafting of MSCs. This theory arose from studies utilizing a myocardial infarction model, in which after MSC injection only a limited number of MSCs were present at the injury site, whereas the fate of the remainder of the cells was unclear (33). Another theoretical clinically relevant risk might be an increase in secondary infections following MSC transplant due to the possible immunosuppressive effects of these cells. In a recent retrospective study, Forslöw et al. (34) demonstrated that MSC treatment in severe graft-versus-host disease was an independent risk factor for overall pneumonia-related death. Of these patients, 32% had a mold infection. These authors indicated that MSCs should be used with caution, and if used, adequate infection control is very important. An additional potential risk is the biosafety of MSC growth medium components. Historically, phase I/II studies involving MSCs in patients with acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantations were performed with fetal calf serum (FCS)–derived MSCs. This was also the case in the study by Forslöw et al. (34). More recently, the international cellular therapy community completely eliminated the use of FCS during the production process of all cellular products used clinically. This approach was taken to minimize unwanted FCS-mediated immunological phenomena and to reduce the risk of transmission of pathogens, including prions and still unidentified zoonoses. Therefore, FCS has been replaced by platelet lysates for the expansion of MSCs in multiple centers (35). As the extrapolation from in vitro and animal studies and from different clinical settings is difficult, the clinical consequences of these risks regarding sepsis remain unpredictable. Currently, the limited clinical trials conducted with autologous or allogeneic MSCs have not reported major health concerns in terms of severe adverse reactions. Altogether, these data suggest that the use of MSC-based therapy is relatively safe.
The studies described above postulate that the signals produced by inflamed tissues may determine MSC functionality. These effects include bacterial clearance, inflammation suppression, antiapoptosis, or stimulation of regenerative responses. We conclude that the clinical application of MSC-based therapies is feasible, is well tolerated, and may have benefits for patients with sepsis. Considering the life-threatening nature of this disease, there is an unmet clinical need in the treatment of severe sepsis or septic shock. This novel treatment approach may be of great medical and socioeconomic significance. As the preclinical data and the data from other clinical conditions that utilize MSC-based therapies cannot be exactly extrapolated as a reason to use for sepsis, clinicians emphasize the need for MSC-based therapy intervention studies within this particular population of sepsis. Many experimental drugs tested in sepsis utilize a 72- to 96-h interval in which an optimal sepsis treatment intervention would most likely be effective. As the evolutionary processes of sepsis lead to the deterioration of a patient’s condition in the first few hours of its onset, an MSC-based therapy might be most helpful if implemented at the disease onset. The start of a new MSC treatment modality for patients with a vulnerable status necessitates the development of a research framework that begins in the laboratory and ends in the clinic. Each process of the treatment modality must be defined, and the corresponding tasks need to be distributed to responsible professionals. Only by taking this approach will the implementation of the knowledge from all stages of MSC product processing, such as manufacturing, preparation for use, clinical application, and trial-related assessments, be achieved. Such a structure will facilitate the integration of any discovered research evidence into clinical practice. The start of the first phase 1 single-center safety and dose escalation trial in Ottawa, by the Canadian Critical Care Trials Group, may clarify the tolerable dose, safety profile, and feasibility of MSC infusions in sepsis patients.
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Immunomodulation; antiapoptosis; bacterial clearance; endothelial/epithelial dysfunction; adult stem cell therapy
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