Antioxidant Levels Represent a Major Determinant in the Regenerative Capacity of Muscle Stem Cells

Abstract

Stem cells are classically defined by their multipotent, long-term proliferation, and self-renewal capabilities. Here, we show that increased antioxidant capacity represents an additional functional characteristic of muscle-derived stem cells (MDSCs). Seeking to understand the superior regenerative capacity of MDSCs compared with myoblasts in cardiac and skeletal muscle transplantation, our group hypothesized that survival of the oxidative and inflammatory stress inherent to transplantation may play an important role. Evidence of increased enzymatic and nonenzymatic antioxidant capacity of MDSCs were observed in terms of higher levels of superoxide dismutase and glutathione, which appears to confer a differentiation and survival advantage. Further when glutathione levels of the MDSCs are lowered to that of myoblasts, the transplantation advantage of MDSCs over myoblasts is lost when transplanted into both skeletal and cardiac muscles. These findings elucidate an important cause for the superior regenerative capacity of MDSCs, and provide functional evidence for the emerging role of antioxidant capacity as a critical property for MDSC survival post-transplantation. INTRODUCTIONMyogenic cell transplantation has been proposed as a promising therapeutic approach in the treatment of skeletal and cardiac muscle injury. Early studies of myoblast transplantation into dystrophic skeletal muscle yielded limited regeneration of dystrophin-expressing muscle fibers (Beauchamp et al., 1994;Gussoni et al., 1997;Qu-Petersen et al., 2002). Similarly, given the limited regenerative ability of cardiac muscle, cell transplantation has been proposed as an alternative to heart transplantation (Assmus et al., 2006;Lunde et al., 2006;Schachinger et al., 2006).A major obstacle in both cardiac and skeletal myogenic therapies is the poor rate of engraftment of myogenic cells after transplantation (Taylor et al., 1998;Oshima et al., 2005). In skeletal muscle, numerous groups have observed a rapid inflammatory response that appears to contribute to rapid cell loss and limit therapeutic success (Beauchamp et al., 1994;Gussoni et al., 1997;Beauchamp et al., 1999). Multiple groups have postulated that the small number of injected cells that survive transplantation in both cardiac and skeletal muscle may represent a special subpopulation of stem-like cells (Qu et al., 1998;Beauchamp et al., 1999;Qu-Petersen et al., 2002).For these reasons, our group attempted to isolate this putative subpopulation of cells using a modified preplate technique. This procedure was initially developed to purify myoblasts from nonmyogenic cells, including fibroblasts, of whole tissue preparations based on the differential adhesion characteristics of the cells to a collagen coated flask (Rando and Blau, 1994). Our group modified this technique to isolate various populations of myogenic cells, including a population of early adhering preplate (EP) cells and a late adhering preplate (LP) cell population from which a subpopulation of long-term proliferating (LTP) cells,...

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