Allogeneic administration of fetal membrane-derived mesenchymal stem cells attenuates acute myocarditis in rats

Abstract 

We reported previously that the autologous administration of bone marrow-derived mesenchymal stem cells (BM-MSC) significantly attenuated myocardial dysfunction and injury in a rat model of acute myocarditis by stimulating angiogenesis and reducing inflammation. Because BM aspiration procedures are invasive and can yield low numbers of MSC after processing, we focused on fetal membranes (FMs) as an alternative source of MSC to provide a large number of cells. We investigated whether the allogeneic administration of FM-derived MSC (FM-MSC) attenuates myocardial injury and dysfunction in a rat myocarditis model. Experimental autoimmune myocarditis (EAM) was induced in male Lewis rats by injecting porcine cardiac myosin. Allogeneic FM-MSC obtained from major histocompatibility complex-mismatched ACI rats (5×10⁵ cells/animal) were injected intravenously into Lewis rats one week after myosin administration. At day 21, severe cardiac inflammation and deterioration of cardiac function were observed. The allogeneic administration of FM-MSC significantly attenuated inflammatory cell infiltration and monocyte chemoattractant protein 1 expression in the myocardium and improved cardiac function. In a T-lymphocyte proliferation assay, the proliferative response of splenic T lymphocytes was significantly lower in cells obtained from FM-MSC-treated EAM rats that reacted to myosin than in cells obtained from vehicle-treated rats with EAM. T-lymphocyte activation was significantly reduced by coculture with FM-MSC. The allogeneic administration of FM-MSC attenuated myocardial dysfunction and inflammation, and the host cell-mediated immune response was attenuated in a rat model of acute myocarditis. These results suggest that allogeneic administration of FM-MSC might provide a new therapeutic strategy for the treatment of acute myocarditis.

Abbreviations: MSC, mesenchymal stem cells, BM, bone marrow, BM-MSC, bone marrow-derived mesenchymal stem cells, FMs, fetal membranes, FM-MSC, fetal membrane-derived mesenchymal stem cells, MHC, major histocompatibility complex, ACI, August–Copenhagen–Irish, GFP, green fluorescent protein, EAM, experimental autoimmune myocarditis, PBS, phosphate-buffered saline, α-MEM, α-minimal essential medium, FBS, fetal bovine serum, TGF-β3, transforming growth factor-β3, FITC, fluorescein isothiocyanate, LVSP, left ventricular systolic pressure, LVDs, left ventricular systolic dimension, LVDd, left ventricular diastolic dimension, H&E, hematoxylin and eosin, MCP1, monocyte chemoattractant protein 1, HRP, horseradish peroxidase

Keywords: Acute myocarditis, Allogeneic transplantation, Fetal membrane, Immunosuppression, Mesenchymal stem cells