Increased survival of muscle stem cells lacking the MyoD gene after transplantation into regenerating skeletal muscle.
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.
Asakura
Atsushi
A
Stem Cell Institute, Paul and Sheila Wellstone Muscular Dystrophy Center, University of Minnesota Medical School, Minneapolis, MN 55455, USA. asakura@umn.edu
Hirai
Hiroyuki
H
Kablar
Boris
B
Morita
Shigeru
S
Ishibashi
Jeff
J
Piras
Bryan A
BA
Christ
Amanda J
AJ
Verma
Mayank
M
Vineretsky
Karin A
KA
Rudnicki
Michael A
MA
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015870:Gene Expression; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000502:physiology*; D017570:MyoD Protein / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D012038:Regeneration / Q000235:genetics*; D032496:Satellite Cells, Skeletal Muscle / Q000502:physiology* / Q000637:transplantation; D033581:Stem Cell Transplantation
D017570:MyoD Protein