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TRANSLATIONAL AND CLINICAL RESEARCH

Secreted Frizzled-Related Protein-1 Enhances Mesenchymal Stem Cell Function in Angiogenesis and Contributes to Neovessel Maturation

^aInstitut National de la Santé et de la Recherche Médicale U828, Université Victor Ségalen, Bordeaux2, Pessac, France;
^bBiochemistry Laboratory, UFR Sciences Pharmaceutiques, Université Victor Ségalen, Bordeaux, France;
^cDepartment of Cardiology, Pole Cardiothoracique, Hôpital Haut Lévêque, Pessac, France

Key Words. Angiogenesis • Cellular therapy • Pericytes • Mesenchymal stem cell

Correspondence: Correspondence: Pascale Dufourcq, Ph.D., Inserm U828, Avenue du Haut Lévèque, 33600 Pessac, France. Telephone: 33557891972; Fax: 3356368979; e-mail: pascale.dufourcq{at}biophar.u-bordeaux2.fr

Received on April 14, 2008; accepted for publication on August 12, 2008.

First published online in STEM CELLS EXPRESS  August 28, 2008.

Mesenchymal stem cell (MSC) transplantation offers a great angiogenic opportunity in vascular regenerative medicine. The canonical Wnt/β-catenin signaling pathway has been demonstrated to play an essential role in stem cell fate. Recently, genetic studies have implicated the Wnt/Frizzled (Fz) molecular pathway, namely Wnt7B and Fz4, in blood growth regulation. Here, we investigated whether MSC could be required in shaping a functional vasculature and whether secreted Frizzled-related protein-1 (sFRP1), a modulator of the Wnt/Fz pathway, could modify MSC capacities, endowing MSC to increase vessel maturation. In the engraftment model, we show that murine bone marrow-derived MSC induced a beneficial vascular effect through a direct cellular contribution to vascular cells. MSC quickly organized into primitive immature vessel tubes connected to host circulation; this organization preceded host endothelial cell (EC) and smooth muscle cell (SMC) recruitment to later form mature neovessel. MSC sustained neovessel organization and maturation. We report here that sFRP1 forced expression enhanced MSC surrounding neovessel, which was correlated with an increase in vessel maturation and functionality. In vitro, sFRP1 strongly increased platelet-derived growth factor-BB (PDGF-BB) expression in MSC and enhanced β-catenin-dependent cell-cell contacts between MSC themselves and EC or SMC. In vivo, sFRP1 increased their functional integration around neovessels and vessel maturation through a glycogen synthase kinase 3 beta (GSK3β)-dependent pathway. sFRP1-overexpressing MSC compared with control MSC were well elongated and in a closer contact with the vascular wall, conditions required to achieve an organized mature vessel wall. We propose that genetically modifying MSC to overexpress sFRP1 may be potentially effective in promoting therapeutic angiogenesis/arteriogenesis processes.

Disclosure of potential conflicts of interest is found at the end of this article.

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