Differentiation, engraftment and functional effects of pre-treated mesenchymal stem cells in a rat myocardial infarct model.
BACKGROUND
Mesenchymal stem cells (MSCs) offer a novel therapeutic option in the treatment of acute myocardial infarction. MSCs are able to differentiate into myogenic cells after 5-azacytitdine treatment. However, 5-azacytidine might have genotoxic effects. Recently, it was reported that combined treatment with bone morphogenetic protein-2(BMP-2) and fibroblast growth factor-4(FGF-4) caused cardiac differentiation in non-precardiac mesoderm explants. Therefore, we investigated whether MSCs treated with combined BMP-2 and FGF-4 showed evidence of myogenic differentiation in vitro, and whether these cells resulted in sustained engraftment, myogenic differentiation, and improved cardiac function after implantation in infarcted myocardium.


RESULTS
In vitro study: MSCs were treated with BMP-2 + FGF-4 (GF-MSCs) and myogenic phenotype was evaluated immunohistochemically. Cell growth curve was used to compare MSC proliferative capacity between the growth factors and 5-azacytidine treatments. In vivo study: two weeks after coronary artery occlusion, GF-MSCs (n=15), MSCs (n=5) labelled with PKH26 were injected into infarcted myocardium. Control animals (n=5) received a culture medium into the infarcted myocardium. Two weeks after implantation, some engrafted GF-MSCs or MSCs expressed sarcomeric-alpha-actinin and cardiac myosin heavy chain, as was observed in culture. Echocardiography showed that the GF-MSC group had a better (p < 0.05) left ventricular performance than the other groups.


CONCLUSIONS
GF-MSCs induced myogenic differentiation in vitro. Moreover, GF-MSCs engrafted into the infarcted myocardium increased myogenic differentiation, prevented dilation of the infarcted region, and eventually improved heart function.
Department of Cardiology, Korea University Medical Center, Korea University, Seoul, Korea.
Jihyun
J
Yoon
Byoung Goo
BG
Min
Young-Hoon
YH
Kim
Wan Joo
WJ
Shim
Young Moo
YM
Ro
Do-Sun
DS
Lim
D000818:Animals; D001374:Azacitidine / Q000494:pharmacology; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D007150:Immunohistochemistry; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects*; D009203:Myocardial Infarction / Q000601:surgery*; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013318:Stroke Volume; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000502:physiology
C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; C496447:Fgf4 protein, rat; D051519:Fibroblast Growth Factor 4; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; D005346:Fibroblast Growth Factors; D001374:Azacitidine