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

OPEN ACCESS ARTICLE

This Article Free via Open Access: OA OA Full Text Full Text (PDF) OA All Versions of this Article: 2007-0388v1 25/12/3234    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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Cai, L. Articles by March, K. L. Search for Related Content PubMed PubMed Citation Articles by Cai, L. Articles by March, K. L.

TISSUE-SPECIFIC STEM CELLS

Suppression of Hepatocyte Growth Factor Production Impairs the Ability of Adipose-Derived Stem Cells to Promote Ischemic Tissue Revascularization

^aIndiana Center for Vascular Biology and Medicine,
^bDepartment of Cellular and Integrative Physiology,
^cKrannert Institute of Cardiology,
^dDepartment of Medical and Molecular Genetics,
^eDepartment of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA;
^fR.L. Roudebush, VA Medical Center, Indianapolis, Indiana, USA

Key Words. Adipose-derived stem cells • RNA interference • Paracrine • Hepatocyte growth factor

Correspondence: Keith L. March, M.D., Ph.D., Indiana Center for Vascular Biology & Medicine, 975 W. Walnut Street IB 441, Indianapolis, Indiana 46202, USA. Telephone: (317) 278-0130; Fax: (317) 278-0089; e-mail: kmarch{at}iupui.edu

Received May 21, 2007; accepted for publication September 10, 2007.
First published online in STEM CELLS EXPRESS   September 27, 2007.



The use of adipose-derived stem/stromal cells (ASCs) for promoting repair of tissues is a promising potential therapy, but the mechanisms of their action are not fully understood. We and others previously demonstrated accelerated reperfusion and tissue salvage by ASCs in peripheral ischemia models and have shown that ASCs secrete physiologically relevant levels of hepatocyte growth factor (HGF) and vascular endothelial growth factor. The specific contribution of HGF to ASC potency was determined by silencing HGF expression. RNA interference was used to downregulate HGF expression. A dual-cassette lentiviral construct expressing green fluorescent protein (GFP) and either a small hairpin RNA specifically targeted to HGF mRNA (shHGF) or an inactive control sequence (shCtrl) were used to stably transduce ASCs (ASC-shHGF and ASC-shCtrl, respectively). Transduced ASC-shHGF secreted >80% less HGF, which led to a reduced ability to promote survival, proliferation, and migration of mature and progenitor endothelial cells in vitro. ASC-shHGF were also significantly impaired, compared with ASC-shCtrl, in their ability to promote reperfusion in a mouse hindlimb ischemia model. The diminished ability of ASCs with silenced HGF to promote reperfusion of ischemic tissues was reflected by reduced densities of capillaries in reperfused tissues. In addition, fewer GFP⁺ cells were detected at 3 weeks in ischemic limbs of mice treated with ASC-shHGF compared with those treated with ASC-shCtrl. These results indicate that production of HGF is important for the potency of ASCs. This finding directly supports the emerging concept that local factor secretion by donor cells is a key element of cell-based therapies.

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

This article has been cited by other articles:

				S. Ishikane, S. Ohnishi, K. Yamahara, M. Sada, K. Harada, K. Mishima, K. Iwasaki, M. Fujiwara, S. Kitamura, N. Nagaya, et al. Allogeneic Injection of Fetal Membrane-Derived Mesenchymal Stem Cells Induces Therapeutic Angiogenesis in a Rat Model of Hind Limb Ischemia Stem Cells, October 1, 2008; 26(10): 2625 - 2633. [Abstract] [Full Text] [PDF]