Enhanced mesenchymal cell engraftment by IGF-1 improves left ventricular function in rats undergoing myocardial infarction.
BACKGROUND
We hypothesized that enhanced mesenchymal cell (MC) engraftment with insulin-like growth factor-1 (IGF-1) improves left ventricular (LV) function and survival.


RESULTS
IGF-1 (10 microg/ml) increased adhesion and inhibited apoptosis under hypoxia in vitro through activation of phosphatidylinositol 3-kinase (PI3K) in bone marrow-derived MCs obtained from transgenic rats expressing green fluorescence protein. Myocardial infarction (MI) in rats was produced by ligature of the left coronary artery. One month after MI, rat hearts were injected with MCs in the presence or absence of 10 microg/ml IGF-1 with or without PI3K inhibitor, 5 microM LY294002. IGF-1 significantly increased engraftment of MCs between 6 h and 3 days after transplantation associated with the increase in stromal cell-derived factor-1alpha in the infracted LV. The transplanted MCs had disappeared 1 month after transplantation in all groups. MC transplantation with IGF-1 significantly increased neovascularization and inhibited cardiomyocyte apoptosis 3 days and 1 month after MC transplantation. This was associated with improved LV function 1 month after MC transplantation and eventually survival. LY294002 abrogated all of the beneficial effects of MC transplantation with IGF-1. IGF-1 alone had no effect on neovascularization and did not improve LV function and/or survival.


CONCLUSIONS
These results suggest that IGF-1 improves engraftment of MCs at the time of transplantation via activation of PI3K and this improved engraftment of MCs may be attributed to an increased neovascularization and inhibition of cardiomyocyte death, leading to improvement of LV function and prolongation of survival despite the eventual loss of the transplanted MCs.
Enoki
Chiharu
C
Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, Moriguchi City, Japan.
Otani
Hajime
H
Sato
Daisuke
D
Okada
Takayuki
T
Hattori
Reiji
R
Imamura
Hiroji
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis; D000860:Hypoxia / Q000188:drug therapy; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016277:Ventricular Function, Left / Q000187:drug effects*
D054377:Chemokine CXCL12; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases