Transfection of mesenchymal stem cells with the FGF-2 gene improves their survival under hypoxic conditions.
Bone marrow mesenchymal stem cells (MSCs) have shown potential for cardiac repair following myocardial injury, but this approach is limited by their poor viability after transplantation. To reduce cell loss after transplantation, we introduced the fibroblast growth factor-2 (FGF-2) gene ex vivo before transplantation. The isolated MSCs produced colonies with a fibroblast-like morphology in 2 weeks; over 95% expressed CD71, and 28% expressed the cardiomyocyte-specific transcription factor, Nkx2.5, as well as a-skeletal actin, Nkx2.5, and GATA4. In hypoxic culture, the FGF-2-transfected MSCs (FGF-2-MSCs) secreted increased levels of FGF-2 and displayed a threefold increase in viability, as well as increased expression of the anti-apoptotic gene, Bcl2, and reduced DNA laddering. They had functional adrenergic receptors, like cardiomyocytes, and exposure to norepinephrine led to phosphorylation of ERK1/2. Viable cells persisted 4 weeks after implantation of 5.0 yen 105 FGF-2-MSCs into infarcted myocardia. Expression of cardiac troponin T (CTn T) and a voltage-gated Ca2+ channel (CaV2.1) increased, and new blood vessels formed. These data suggest that genetic modification of MSCs before transplantation could be useful for treating myocardial infarction and end-stage cardiac failure.
Song
Heesang
H
Cardiovascular Research Institute, Brain Korea 21 Project for Medical Science, Cardiology Division, Yonsei University College of Medicine, Seoul 120-752, Korea.
Kwon
Kihwan
K
Lim
Soyeon
S
Kang
Seok-Min
SM
Ko
Young-Guk
YG
Xu
Zhengzhe
Z
Chung
Ji Hyung
JH
Kim
Byung-Soo
BS
Lee
Hakbae
H
Joung
Boyoung
B
Park
Sungha
S
Choi
Donghoon
D
Jang
Yangsoo
Y
Chung
Nam-Sik
NS
Yoo
Kyung-Jong
KJ
Hwang
Ki-Chul
KC
D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D002470:Cell Survival / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D009203:Myocardial Infarction / Q000503:physiopathology / Q000601:surgery; D018919:Neovascularization, Physiologic / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
D016222:Fibroblast Growth Factor 2; D048049:Extracellular Signal-Regulated MAP Kinases