Beating is necessary for transdifferentiation of skeletal muscle-derived cells into cardiomyocytes.
Cell transplantation could be a potential therapy for heart damage. Skeletal myoblasts have been expected to be a good cell source for autologous transplantation; however, the safety and efficacy of their transplantation are still controversial. Recent studies have revealed that skeletal muscle possesses the stem cell population that is distinct from myoblasts. To elucidate whether skeletal muscle stem cells can transdifferentiate into cardiomyocytes, we cocultured skeletal muscle cells isolated from transgenic mice expressing green fluorescent protein with cardiomyocytes of neonatal rats. Skeletal muscle-derived cells expressed cardiac-specific proteins such as cardiac troponin T and atrial natriuretic peptide as well as cardiac-enriched transcription factors such as Nkx2E (formerly called Csx/Nkx2.5) and GATA4 by coculture with cardiomyocytes. Skeletal muscle-derived cells also expressed cadherin and connexin 43 at the junctions with neighboring cardiomyocytes. Cardiomyocyte-like action potentials were recorded from beating skeletal muscle-derived cells. Treatment of nifedipine or culture in Ca2+-free media suppressed contraction of cardiomyocytes and inhibited skeletal muscle cells to express cardiac-specific proteins. Cyclic stretch completely restored this inhibitory effect. These results suggest that some part of skeletal muscle cells can transdifferentiate into cardiomyocytes and that direct cell-to-cell contact and contraction of neighboring cardiomyocytes are important for the transdifferentiation.
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
Yoshihiro
Y
Iijima
Toshio
T
Nagai
Miho
M
Mizukami
Katsuhisa
K
Matsuura
Takehiko
T
Ogura
Hiroshi
H
Wada
Haruhiko
H
Toko
Hiroshi
H
Akazawa
Hiroyuki
H
Takano
Haruaki
H
Nakaya
Issei
I
Komuro
D000200:Action Potentials; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002450:Cell Communication; D002454:Cell Differentiation / Q000187:drug effects; D018920:Coculture Techniques; D018031:Connexin 43 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D050991:GATA4 Transcription Factor; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism; D007365:Intercellular Junctions / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000166:cytology*; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology; D051381:Rats; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D020107:Troponin T / Q000378:metabolism; D029867:Xenopus Proteins
D015820:Cadherins; D018031:Connexin 43; D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors; D020107:Troponin T; D029867:Xenopus Proteins; D009320:Atrial Natriuretic Factor; D009543:Nifedipine