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Abstract
BackgroundIt is known that, following a physiological insult, bone marrow-derived mesenchymal stem cells (MSCs) mobilize and home to the site of injury. However, the effect of injury on the function of endogenous MSCs is unknown. In this study, MSCs harvested from the bone marrow of swine with or without acute respiratory distress syndrome (ARDS) were assessed for their characteristics and therapeutic function.MethodsMSCs were harvested from three groups of anesthetized and mechanically ventilated swine (n = 3 in each group): 1) no ARDS (‘Uninjured’ group); 2) ARDS induced via smoke inhalation and 40% burn and treated with inhaled epinephrine (‘Injured Treated’ group); and 3) ARDS without treatment (‘Injured Untreated’ group). Cellular evaluation of the three groups included: flow cytometry for MSC markers; colony forming unit-fibroblast (CFU-F) assay; proliferative and metabolic capacity; gene expression using quantitative real-time polymerase chain reaction (qRT-PCR); and a lipopolysaccharide (LPS) challenge, with or without coculture with mononuclear cells (MNCs), for evaluation of their protein secretion profile using Multiplex. Statistical analysis was performed using one- or two-way analysis of variance (ANOVA) with a Tukey’s post-test; a p-value less than 0.05 was considered statistically significant.ResultsCells from all groups exhibited nearly 100% expression of MSC surface markers and retained their multidifferentiation capacity. However, the MSCs from the ‘Injured Untreated’ group generated a significantly higher number of colonies compared with the other two groups (p < 0.0001), indicative of increased clonogenic capacity following ARDS. Following an LPS challenge, the MSCs from the ‘Injured Untreated’ group exhibited a significant reduction in their proliferative capacity (p = 0.0002), significant downregulation in the expression of high-mobility group box 1 (HMGB1; p < 0.001), Toll-like receptor (TLR)-4 (p < 0.01), and vascular endothelial growth factor (VEGF; p < 0.05) genes, and significantly diminished secretory capacity for the inflammatory mediators interleukin (IL)-6 (p < 0.0001), IL-8 (p < 0.05), and tumor necrosis factor (TNF)-α (p < 0.05) compared with the ‘Uninjured’ group.ConclusionsThe results suggest that, following ARDS, there is an increase in the clonogenic capacity of MSCs to increase the available stem cell pool in vivo. However, MSCs harvested from subjects with ARDS seem to exhibit a diminished capacity to proliferate, express regenerative signals, and secrete pro/anti-inflammatory mediators.
Highlights
It is known that, following a physiological insult, bone marrow-derived mesenchymal stem cells (MSCs) mobilize and home to the site of injury
Functional characteristics of MSCs The effect of acute respiratory distress syndrome (ARDS) on the characteristics and function of bone marrow MSCs was evaluated using a panel of in-vitro assays
Therapy (ISCT), the minimal criteria to define MSCs are: adherence to plastic; expression of specific surface markers; and the ability to differentiate to osteocytes, adipocytes, and chondrocytes in vitro [8]
Summary
It is known that, following a physiological insult, bone marrow-derived mesenchymal stem cells (MSCs) mobilize and home to the site of injury. MSCs harvested from the bone marrow of swine with or without acute respiratory distress syndrome (ARDS) were assessed for their characteristics and therapeutic function. Mesenchymal stem cells (MSCs) have emerged as a potent therapeutic tool for treating acute respiratory distress syndrome (ARDS), as exemplified by their abundant use in numerous preclinical animal studies as well as early-phase clinical trials. Since the hallmark of ARDS is an acute inflammatory response, bioactive factors secreted by MSCs are expected to immuno-modulate the inflammatory response seen in ARDS. This inflammatory process can be modeled in vitro via exposure to lipopolysaccharide (LPS), an endotoxin secreted by gram-negative bacteria which mimics infection, the most common etiology of ARDS [1]. Autologous transplantation circumvents the risks and potential complications associated with allogeneic therapy, such as those occurring from a donor mismatch or disease transmission
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