HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 2008-0369v1 26/10/2634    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ben-Shoshan, J. Articles by George, J. Search for Related Content PubMed PubMed Citation Articles by Ben-Shoshan, J. Articles by George, J.

TISSUE-SPECIFIC STEM CELLS

Constitutive Expression of HIF-1 and HIF-2 in Bone Marrow Stromal Cells Differentially Promotes Their Proangiogenic Properties

^aDepartment of Cardiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel;
^bSackler School of Medicine, Tel Aviv University, Tel Aviv, Israel;
^cDepartment of Ophthalmology, Assaf Harofeh Medical Center, Zrifin, Israel;
^dInstitute of Pathology, and
^eInstitute of Ophthalmology, Sheba Medical Center, Tel Hashomer, Israel;
^fDepartment of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel;
^gDepartment of Ophthalmology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

Key Words. Bone marrow stromal cells • Hypoxia-inducible factor • Angiogenesis • Paracrine effects • Cell therapy

Correspondence: Correspondence: Prof. Jacob George, M.D., Department of Cardiology, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel. Telephone: 972-3-6974250; Fax: 972-3-6974808; e-mail: jacobg{at}post.tau.ac.il

Received on April 18, 2008; accepted for publication on July 28, 2008.

First published online in STEM CELLS EXPRESS  August 7, 2008.

Bone marrow stromal cells (BMSCs) contain progenitors capable of participating in postnatal angiogenesis. Hypoxia-inducible factors (HIFs) mediate endothelial activation by driving the expression of multiple angiogenic factors. We explored the potential of HIF-1 and HIF-2 modification in BMSCs, as a tool to improve cell-based angiogenic therapy. BMSCs were retrovirally transduced to express stable forms of HIF-1 and HIF-2. HIF-1 and, to a greater extent, HIF-2 overexpression promoted differentiation of BMSCs to the endothelial lineage, evident by CD31 and Tie-2 expression and improved adhesive properties. Whereas chemotaxis toward stromal-derived factor 1 was higher in both HIF--expressing BMSCs, enhanced migration toward vascular endothelial growth factor was found only following overexpression of HIF-2, supported by a robust expression of its receptor, Flk-1. HIF- expression was associated with upregulation of angiogenic proteins and improved tube formation. Cytokine arrays of endothelial cells stimulated by medium collected from HIF--expressing BMSCs revealed further angiogenic activation and improved adhesive capacity. Eventually, delivery of HIF-2-transduced BMSCs induced a more robust angiogenic response, compared with sham-transduced or HIF-1-transduced BMSCs in the corneal micropocket angiogenesis model. Our results support the use of HIF- genes, particularly HIF-2, to augment the efficacy of future cell-based therapy.

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