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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

Joo-Yong Hahn, MD, PhD^_*,, Hyun-Ju Cho, MS^_*, Hyun-Jae Kang, MD, PhD^_*,,_*, Tack-Seung Kim, MS, Mi-Hyung Kim, PhD, Jung-Hwa Chung, MD^_*, Jang-Whan Bae, MD, PhD^_*, Byung-Hee Oh, MD, PhD^_*,, Young-Bae Park, MD, PhD^_*, and Hyo-Soo Kim, MD, PhD^_*,,_*

^_* National Research Laboratory for Cardiovascular Stem Cells, Seoul National University College of Medicine, Seoul, Republic of Korea
Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea
Anterogen Corp., Seoul, Republic of Korea.

Manuscript received August 20, 2007; revised manuscript received October 26, 2007, accepted November 27, 2007.

^_* Reprint requests and correspondence: Dr. Hyo-Soo Kim Dr. Hyun-Jae Kang, Department of Internal Medicine, Seoul National University College of Medicine, 28 Yeongun-dong, Chongro-gu, Seoul, 110-744, Korea. (Email: nowkang{at}snu.ac.kr).

Objectives: 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.

Abbreviations and Acronyms   BMP = bone morphogenetic protein   CMC = cardiomyocyte   DMEM = Dulbecco’s Modified Eagle Medium   FACS = fluorescence-activated cell sorter   FBS = fetal bovine serum   FGF = fibroblast growth factor   FS = fractional shortening   GF = growth factor   IGF = insulin-like growth factor   LV = left ventricle/ventricular   LVEDD = left ventricular end-diastolic dimension   LVESD = left ventricular end-systolic dimension   MEF = myocyte enhancer factor   MI = myocardial infarction   MSC = mesenchymal stem cell   RT-PCR = reverse transcriptase-polymerase chain reaction   VF = ventricular fibrillation

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