Pre-treatment of mesenchymal stem cells with a combination of growth factors enhances gap junction formation, cytoprotective effect on cardiomyocytes, and therapeutic efficacy for myocardial infarction.
OBJECTIVE
The goal of this study was to investigate the effect of pre-treatment of mesenchymal stem cells (MSCs) with growth factors (GFs) on cardiomyogenic differentiation, cytoprotective action on cardiomyocytes (CMCs), and their therapeutic efficacy in myocardial infarction.


BACKGROUND
Mechanisms of myocardial repair with MSC transplantation have not been fully elucidated, and therapeutic efficacy needs to be enhanced.


METHODS
The MSCs obtained from the bone marrow of Fisher344 rats were treated with fibroblast growth factor-2, insulin-like growth factor-1, and bone morphogenetic protein-2. The expression of cardiac specific markers and the cytoprotective effect of MSCs with its mechanism were evaluated. Efficacy of MSCs transplantation was studied in rat myocardial infarction model.


RESULTS
Treatment of MSCs with cocktails of GFs enhanced expression of cardiac transcription factors and survival. Induction of cardiac specific markers by coculture with CMCs and gap junctional communication with CMCs was more active in GF-treated MSCs than untreated MSCs. The GF-treated MSCs reduced apoptosis of neighboring CMCs in a hypoxic condition and enhanced the phosphorylated Akt and phosphorylated c-AMP response element binding protein expression of CMCs, which was markedly reduced by gap junction blockade. In a rat myocardial infarction model, transplantation of GF-treated MSCs resulted in smaller infarct size and better cardiac function than transplantation of untreated MSCs. Additionally, GF treatment enhanced gap junction formation of transplanted MSCs, which did not aggravate arrhythmia.


CONCLUSIONS
Pre-treatment of MSCs with GFs enhanced cytoprotective effects on neighboring CMCs through gap junction and improved the therapeutic efficacy of MSC transplantation for myocardial repair. "Priming of MSCs with GFs" before transplantation might improve the therapeutic efficacy of cell therapy.
Hahn
Joo-Yong
JY
National Research Laboratory for Cardiovascular Stem Cells, Seoul National University College of Medicine, Seoul, Republic of Korea.
Cho
Hyun-Ju
HJ
Kang
Hyun-Jae
HJ
Kim
Tack-Seung
TS
Kim
Mi-Hyung
MH
Chung
Jung-Hwa
JH
Bae
Jang-Whan
JW
Oh
Byung-Hee
BH
Park
Young-Bae
YB
Kim
Hyo-Soo
HS
D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects*; D009203:Myocardial Infarction / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2; D007334:Insulin-Like Growth Factor I