Hyaluronan Mixed Esters of Butyric and Retinoic Acid Affording Myocardial Survival and Repair without Stem Cell Transplantation

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.

Sodium butyrate inhibits platelet‐derived growth factor‐induced proliferation and migration in pulmonary artery smooth muscle cells through Akt inhibition

“…Protein samples were prepared and immunoblots were analyzed as previously described [33]. Briefly, cells were lysed with M-PER extraction buffer supplemented with 1 mM phenylmethanesulfonyl fluoride, protease, and phosphatase inhibitor cocktail (Sigma-Aldrich).…”

Cancer Stem Cells: Foe or Reprogrammable Cells for Efficient Cancer Therapy?

“…Preconditioning with HBR of hMSCs ex vivo has also greatly increased the ability of these cells to repair infarcted hearts in both small (rats) and large (pig) animal models of post-infarct heart failure [35,53]. In subsequent studies, we have shown that the intramyocardial injection of HBR alone was even able to induce a substantial repair of the infarcted myocardial tissue, by acting on endogenous mechanisms of tissue regeneration and recruitment/activation of endogenous stem cells, without having to resort to stem cell transplantation [54].…”

Seeing Cell Biology with the Eyes of Physics

“…This finding points at the relevant pleiotropic role of hyaluronic acid (HA) and glycosaminoglycans in the intracrine regulation of cell polarity and at the chance of using physical energies to preserve and direct this fundamental attribute of Life. HA has been used as a component to promote cardiogenesis in mouse embryonic [42] and human adult stem cells of different origin in vitro and in vivo [43][44][45] and to induce cardiac repair in vivo without stem cell transplantation in a rat model of myocardial infarction [46]. Accordingly, HAS2 suppression abolished the capability of human ES cells to differentiate in vitro along the cardiogenic and vasculogenic lineages [47].…”