Abstract
BackgroundThe capacity of muscle to grow or to regenerate after damage is provided by adult stem cells, so called satellite cells, which are located under the basement lamina of each myofiber. Upon activation satellite cells enter the cell cycle, proliferate and differentiate into myoblasts, which fuse to injured myofibers or form new fibers. These processes are tightly controlled by many growth factors.ResultsHere we investigate the role of bone morphogenetic proteins (BMPs) during satellite cell differentiation. Unlike the myogenic C2C12 cell line, primary satellite cells do not differentiate into osteoblasts upon BMP signaling. Instead BMP signaling inhibits myogenic differentiation of primary satellite cells ex vivo. In contrast, inhibition of BMP signaling results in cell cycle exit, followed by enhanced myoblast differentiation and myotube formation. Using an in vivo trauma model we demonstrate that satellite cells respond to BMP signals during the regeneration process. Interestingly, we found the BMP inhibitor Chordin upregulated in primary satellite cell cultures and in regenerating muscles. In both systems Chordin expression follows that of Myogenin, a marker for cells committed to differentiation.ConclusionOur data indicate that BMP signaling plays a critical role in balancing proliferation and differentiation of activated satellite cells and their descendants. Initially, BMP signals maintain satellite cells descendants in a proliferating state thereby expanding cell numbers. After cells are committed to differentiate they upregulate the expression of the BMP inhibitor Chordin thereby supporting terminal differentiation and myotube formation in a negative feedback mechanism.
Highlights
The capacity of muscle to grow or to regenerate after damage is provided by adult stem cells, so called satellite cells, which are located under the basement lamina of each myofiber
We found that bone morphogenetic proteins (BMPs) keep satellite cell descendants in a proliferating state, while cell cycle exit and myotube formation is induced by inhibition of BMP signaling
Inhibition of BMP signaling triggers myogenic differentiation in C2C12 cells To gain first insight into a potential role of BMP signaling during satellite cell differentiation we examined myogenic differentiation of C2C12 cells after treatment with Bmp7 and Noggin (Figure 1; n = 6)
Summary
The capacity of muscle to grow or to regenerate after damage is provided by adult stem cells, so called satellite cells, which are located under the basement lamina of each myofiber. Upon activation satellite cells enter the cell cycle, proliferate and differentiate into myoblasts, which fuse to injured myofibers or form new fibers. These processes are tightly controlled by many growth factors. Adult muscle tissue is characterized by its capacity to grow after exercise and to regenerate after injury Both processes require stem cells - so called satellite cells, which are located between the myofiber membrane and the surrounding basement lamina [1]. While most of the satellite cell descendants are committed to differentiate, either by fusing to existing fibers or by forming new myofibers, some of these cells do not enter the differentiation program, but exit the cell cycle and During satellite cell differentiation distinct phases can be distinguished, which are characterized by the expression of different transcription factors. Based on the expression of these transcription factors adult regenerative myogenesis largely recapitulates the embryonic and fetal program of muscle differentiation
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