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BIOLOGICAL SCIENCES / CELL BIOLOGY
Increased survival of muscle stem cells lacking the MyoD gene after transplantation into regenerating skeletal muscle
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*Stem Cell Institute, Paul and Sheila Wellstone Muscular Dystrophy Center, and Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455; Molecular Medicine Program, Ottawa Health Research Institute, Ottawa, ON, Canada K1H 8L6; and ||Department of Anatomy and Neurobiology, Dalhousie University Faculty of Medicine, Halifax, NS, Canada B3H 4H7
Communicated by Louis M. Kunkel, Harvard Medical School, Boston, MA, August 29, 2007 (received for review February 22, 2007)
MyoD is a myogenic master transcription factor that plays an essential role in muscle satellite cell (muscle stem cell) differentiation. To further investigate the function of MyoD in satellite cells, we examined the transplantation of satellite cell-derived myoblasts lacking the MyoD gene into regenerating skeletal muscle. After injection into injured muscle, MyoD–/– myoblasts engrafted with significantly higher efficiency compared with wild-type myoblasts. In addition, MyoD–/– myoblast-derived satellite cells were detected underneath the basal lamina of muscle fibers, indicating the self-renewal property of MyoD–/– myoblasts. To gain insights into MyoD gene deficiency in muscle stem cells, we investigated the pathways regulated by MyoD by GeneChip microarray analysis of gene expression in wild-type and MyoD–/– myoblasts. MyoD deficiency led to down-regulation of many muscle-specific genes and up-regulation of some stem cell markers. Importantly, in MyoD–/– myoblasts, many antiapoptotic genes were up-regulated, whereas genes known to execute apoptosis were down-regulated. Consistent with these gene expression profiles, MyoD–/– myoblasts were revealed to possess remarkable resistance to apoptosis and increased survival compared with wild-type myoblasts. Forced expression of MyoD or the proapoptotic protein Puma increased cell death in MyoD–/– myoblasts. Therefore, MyoD–/– myoblasts may preserve stem cell characteristics, including their resistance to apoptosis, expression of stem cell markers, and efficient engraftment and contribution to satellite cells after transplantation. Furthermore, our data offer evidence for improved therapeutic stem cell transplantation for muscular dystrophy, in which suppression of MyoD in myogenic progenitors would be beneficial to therapy by providing a selective advantage for the expansion of stem cells.
apoptosis | cell therapy | microarrays | muscular dystrophy | satellite cell
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0708145104/DC1.
¶To whom correspondence should be addressed. E-mail: asakura{at}umn.edu
© 2007 by The National Academy of Sciences of the USA
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