Human adult skeletal muscle stem cells differentiate into cardiomyocyte phenotype in vitro.
Cell transplantation to repair or regenerate injured myocardium is a new frontier in the treatment of cardiovascular disease. Most studies on stem cell transplantation therapy in both experimental heart infarct and in phase-I human clinical trials have focused on the use of undifferentiated stem cells. Based on our previous observations demonstrating the presence of multipotent progenitor cells in human adult skeletal muscle, in this study we investigated the capacity of these progenitors to differentiate into cardiomyocytes. Here we show an efficient protocol for the cardiomyogenic differentiation of human adult skeletal muscle stem cells in vitro. We found that treatment with Retinoic Acid directed cardiomyogenic differentiation of skeletal muscle stem cells in vitro. After Retinoic Acid treatment, cells expressed cardiomyocyte markers and acquired spontaneous contraction. Functional assays exhibited cardiac-like response to increased extracellular calcium. When cocultured with mouse cardiomyocytes, Retinoic Acid-treated skeletal muscle stem cells expressed connexin43 and when transplanted into ischemic heart were detectable even 5 weeks after injection. Based on these results, we can conclude that human adult skeletal muscle stem cells, if opportunely treated, can transdifferentiate into cells of cardiac lineage and once injected into infarcted heart can integrate, survive in cardiac tissue and improve the cardiac function.
Invernici
Gloria
G
Neurobiology and Neuroregenerative Therapies Unit, Fondazione IRCCS Neurological Institute C. Besta, Milan #20133, Italy. gloria.invernici@istituto-besta.it
Cristini
Silvia
S
Madeddu
Paolo
P
Brock
Stefano
S
Spillmann
Frank
F
Bernasconi
Pia
P
Cappelletti
Cristina
C
Calatozzolo
Chiara
C
Fascio
Umberto
U
Bisleri
Gianluigi
G
Muneretto
Claudio
C
Alessandri
Giulio
G
Parati
Eugenio A
EA
D000328:Adult; D000368:Aged; D000818:Animals; D000077214:Becaplermin; D002454:Cell Differentiation; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000166:cytology* / Q000378:metabolism; D017202:Myocardial Ischemia / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D014212:Tretinoin