Combining neuropeptide Y and mesenchymal stem cells reverses remodeling after myocardial infarction.
Neuropeptide Y (NPY) induced reentry of differentiated rat neonatal and adult cardiomyocytes into the cell cycle. NPY also induced differentiation of bone marrow-derived mesenchymal stem cells (MSC) into cardiomyocytes following transplantation into infarcted myocardium. Rat neonatal and adult cardiomyocytes were treated in vitro with vehicle, NPY, fibroblast growth factor (FGF; 100 ng/ml), or FGF plus NPY. DNA synthesis, mitosis, and cytokinesis were determined by immunocytochemistry. NPY-induced MSC gene expression, cell migration, tube formation, and endothelial cell differentiation were analyzed. Male rat green fluorescent protein-MSC (2 x 10(6)), pretreated with either vehicle or NPY (10(-8) M) for 72 h, were injected into the border zone of the female myocardium following left anterior descending artery ligation. On day 30, heart function was assessed, and hearts were harvested for histological and immunohistochemical analyses. NPY increased 5-bromo-2'-deoxy-uridine incorporation and promoted both cytokinesis and mitosis in rat neonatal and adult myocytes. NPY also upregulated several genes required for mitosis in MSC, including aurora B kinase, FGF-2, cycline A2, eukaryotic initiation factor 4 E, and stromal cell-derived factor-1alpha. NPY directly induced neonatal and adult cardiomyocyte cell-cycle reentry and enhanced the number of differentiated cardiomyocytes from MSC in the infarcted myocardium, which corresponded to improved cardiac function, reduced fibrosis, ventricular remodeling, and increased angiomyogenesis. It is concluded that a combined treatment of NPY with MSC is a novel approach for cardiac repair.
Wang
Yigang
Y
Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267-0529, USA. yi-gang.wang@uc.edu
Zhang
Dongsheng
D
Ashraf
Muhammad
M
Zhao
Tiemin
T
Huang
Wei
W
Ashraf
Atif
A
Balasubramaniam
Ambikaipakan
A
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D006334:Heart Function Tests; D000860:Hypoxia / Q000473:pathology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects; D009203:Myocardial Infarction / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009478:Neuropeptide Y / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology*
C527276:CXCR4 protein, human; D009478:Neuropeptide Y; D019718:Receptors, CXCR4; D042461:Vascular Endothelial Growth Factor A