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J. Biol. Chem., Vol. 282, Issue 19, 14243-14252, May 11, 2007

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Hyaluronan Mixed Esters of Butyric and Retinoic Acid Drive Cardiac and Endothelial Fate in Term Placenta Human Mesenchymal Stem Cells and Enhance Cardiac Repair in Infarcted Rat Hearts^*

Carlo Ventura¹, Silvia Cantoni, Francesca Bianchi, Vincenzo Lionetti, Claudia Cavallini, Ignazio Scarlata, Laura Foroni^¶, Margherita Maioli^||, Laura Bonsi^**, Francesco Alviano^**, Valentina Fossati^**, Gian Paolo Bagnara^**, Gianandrea Pasquinelli^¶, Fabio A. Recchia, and Alberto Perbellini

From the Laboratory of Molecular Biology and Stem Cell Engineering, Institute of Cardiology, National Institute of Biostructures and Biosystems, University of Bologna, I-40138 Bologna, Italy, ^¶Department of Experimental Pathology, University of Bologna, I-40138 Bologna, Italy, ^**Department of Histology, Embryology, and Applied Biology, University of Bologna, I-40138 Bologna, Italy, Sector of Medicine, Scuola Superiore S. Anna, CNR Institute of Clinical Physiology, I-56124 Pisa, Italy and Department of Physiology, New York Medical College, Valhalla, New York 10595, and ^||Department of Biomedical Sciences, University of Sassari, I-07100 Sassari, Italy

We have developed a mixed ester of hyaluronan with butyric and retinoic acid (HBR) that acted as a novel cardiogenic/vasculogenic agent in human mesenchymal stem cells isolated from bone marrow, dental pulp, and fetal membranes of term placenta (FMhMSCs). HBR remarkably enhanced vascular endothelial growth factor (VEGF), KDR, and hepatocyte growth factor (HGF) gene expression and the secretion of the angiogenic, mitogenic, and antiapoptotic factors VEGF and HGF, priming stem cell differentiation into endothelial cells. HBR also increased the transcription of the cardiac lineage-promoting genes GATA-4 and Nkx-2.5 and the yield of cardiac markerexpressing cells. These responses were notably more pronounced in FMhMSCs. FMhMSC transplantation into infarcted rat hearts was associated with increased capillary density, normalization of left ventricular function, and significant decrease in scar tissue. Transplantation of HBR-preconditioned FMhM-SCs further enhanced capillary density and the yield of human vWF-expressing cells, additionally decreasing the infarct size. Some engrafted, HBR-pretreated FMhMSCs were also positive for connexin 43 and cardiac troponin I. Thus, the beneficial effects of HBR-exposed FMhMSCs may be mediated by a large supply of angiogenic and antiapoptotic factors, and FMhMSC differentiation into vascular cells. These findings may contribute to further development in cell therapy of heart failure.

Received for publication, October 3, 2006 , and in revised form, March 9, 2007.

^* This work was supported by Fondazione Luisa Fanti Melloni, Bologna, Italy, Fondazione AlmaMedicina, University of Bologna, Bologna Italy, Tavola Valdese, Rome, Italy, Regione Emilia Romagna, Italy (Programma Regionale per la Ricerca Industriale, l'Innovazione e il Trasferimento Tecnologico), and Compagnia di S. Paolo, Torino, Italy. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–4.

¹ To whom correspondence should be addressed: Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems, University of Bologna, S. Orsola-Malpighi Hospital, Institute of Cardiology, Pavilion 21, Via Massarenti N. 9, 40138 Bologna, Italy. Tel.: 39-051-340339; Fax: 39-051-344859; E-mail: cvent{at}libero.it or carlo.ventura{at}unibo.it.

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