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.
Yoon
Jihyun
J
Department of Cardiology, Korea University Medical Center, Korea University, Seoul, Korea.
Min
Byoung Goo
BG
Kim
Young-Hoon
YH
Shim
Wan Joo
WJ
Ro
Young Moo
YM
Lim
Do-Sun
DS
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