Abstract
Possible cardiac repair by adult stem cell transplantation is currently hampered by poor cell viability and delivery efficiency, uncertain differentiating fate in vivo, the needs of ex vivo cell expansion, and consequent delay in transplantation after the onset of heart attack. By the aid of magnetic resonance imaging, positron emission tomography, and immunohistochemistry, we show that injection of a hyaluronan mixed ester of butyric and retinoic acid (HBR) into infarcted rat hearts afforded substantial cardiovascular repair and recovery of myocardial performance. HBR restored cardiac [18F]fluorodeoxyglucose uptake and increased capillary density and led to the recruitment of endogenous Stro-1-positive stem cells. A terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assay demonstrated that HBR-treated hearts exhibited a decrease in the number of apoptotic cardiomyocytes. In isolated rat cardiomyocytes and Stro-1 stem cells, HBR enhanced the transcription of vascular endothelial growth factor, hepatocyte growth factor, kdr, akt, and pim-1. HBR also increased the secretion of vascular endothelial growth factor and hepatocyte growth factor, suggesting that the mixed ester may have recruited both myocardial and Stro-1 cells also. An increase in capillarogenesis was induced in vitro with medium obtained from HBR-exposed cells. In the infarcted myocardium, HBR injection increased histone H4 acetylation significantly. Acetyl-H4 immunoreactivity increased in rat cardiomyocytes and Stro-1 cells exposed to HBR, compared with untreated cells. In conclusion, efficient cardiac regenerative therapy can be afforded by HBR without the need of stem cell transplantation or vector-mediated gene delivery.
Highlights
Engineering, Cardiovascular Department-National Institute of Biostructures and Biosystems, S
The glycoconjugate hyaluronan with butyric and retinoic acid (HBR) is an ester between the hydroxyl groups of hyaluronan (HA) and the carboxyl groups of both butyric acid (BU) and retinoic acid (RA)
The HBR action involved an early increase in the number of pericytes, a reserve of progenitor cells that may be integral to the origin of MSCs and other related adult stem cells [12], suggesting a role of perivascular cells in capillary density enhancement and tissue repair elicited by the mixed ester
Summary
Analysis of the rescuing potential associated with transplantation of human mesenchymal stem cells (hMSCs) in animal models of MI has recently led to the conclusion that paracrine actions exerted by adult stem cells through the release of soluble factors might be important mechanisms of tissue repair and functional improvement [1, 2] To this end, we have recently shown that hMSCs isolated from fetal membranes of human term placenta (FMhMSCs) secreted large amounts of angiogenic, mitogenic, antiapoptotic, and antifibrotic factors, as compared with hMSCs isolated from the human bone marrow, significantly contributing to improved cardiovascular function in infarcted rat hearts [3]. We directly injected HBR into the myocardium of infarcted rat hearts and provide evidence that the mixed ester afforded substantial recovery of myocardial performance without the need of stem cell transplantation. These responses probably involved the activation of a gene program of paracrine patterning for myocardial protection and angiogenesis and the enhanced survival of locally recruited stem cells
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