Hyaluronan mixed esters of butyric and retinoic acid affording myocardial survival and repair without stem cell transplantation.

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 for 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 Imaging, 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 recover of myocardial performance. HBR restored cardiac 18F-FDG uptake, increased capillary density and led to the recruitment of endogenous Stro-1-positive stem cells. TUNEL 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 VEGF, HGF, KDR, Akt, and Pim-1. HBR also increased the secretion of VEGF and HGF, suggesting that the mixed ester may have recruited both myocardial and Stro-1 cells into a pro-angiogenic paracrine circuitry of cardiac repair. An increase in capillarogenesis was induced in vitro with medium obtained from HBR-exposed cells. In the infarcted heart tissue, HBR injection increased histone H4 acetylation, as compared with non-injected samples. Acetyl-H4 immunoreactivity was also higher in rat cardiomyocytes and Stro-1 cells exposed to HBR, compared to untreated cells. In conclusion, efficient amelioration of cardiac function can be afforded by HBR without the need of stem cell transplantation or vector-mediated gene delivery. The current findings may pave new perspectives in regenerative medicine.