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TISSUE-SPECIFIC STEM CELLS |
1 Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, IN.; Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN.
2 Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, IN.; Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN.
3 Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, IN.; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN.
4 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN.
5 Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, IN.; Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN.
6 Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, IN.; Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN.; R.L. Roudebush VA Medical Center, Indianapolis, IN 46202
* To whom correspondence should be addressed. E-mail: kmarch{at}iupui.edu.
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Abstract |
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Background: 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 VEGF. The specific contribution of HGF to ASC potency was determined by silencing HGF expression.
Methods and Results: RNA interference (RNAi) was used to down-regulate HGF expression. A dual-cassette lentiviral construct expressing GFP and either a small hairpin RNA (shRNA) 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 to 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 wk in ischemic limbs of mice treated with ASC-shHGF compared those treated with ASC-shCtrl.
Conclusions: 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.
Key Words. Adipose-derived stem cells, RNAi, paracrine, hepatocyte growth factor
This article has been cited by other articles:
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  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]
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