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

Abstract

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 ASCshCtrl, 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 ASCshHGF 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. STEM CELLS 2007;25:3234 -3243 Disclosure of potential conflicts of interest is found at the end of this article.

Therapeutic Effects of Mouse Adipose-Derived Stem Cells and Losartan in the Skeletal Muscle of Injured Mdx Mice

“…The activity of the mTOR signaling pathway can be modulated by a variety of factors and pathways acting on different steps, and mTORC1 was activated by the binding of IGF1 to its receptor (40,43). After transplantation, ASCs remained viable at the injured site and secreted growth factors in a continuous and regulated manner in response to the environmental cues, including IGF (2,5,9,14,(22)(23)(24)37,44,46). We thus concluded that the increased muscle size, wet weight, and area of the myofibers in the ASC-transplanted groups are due to the following mechanism: The transplanted ASCs secrete growth factors; those stimulate the mTOR signaling pathway, which activates the synthesis of protein and muscle hypertrophy.…”

“…3E, F). ASCs remained viable after transplantation and secreted a variety of growth factors and cytokines, which activated the differentiation of satellite cells to myoblasts and from myoblasts to myotubes at the injured site (2,5,9,14,(22)(23)(24)37,44,46). The myogenic effect of these growth factors and cytokines might increase the number of myogenin-expressing myocytes.…”

In VitroCharacterization of Patches of Human Mesenchymal Stromal Cells

“…We demonstrated that both BM-dMSC and ASC adherent to the AM secrete high amounts of VEGF-A, IL-8, and HGF, which are known to be important for neovascularization. 6,[41][42][43] Furthermore, adherent MSC secrete antiinflammatory cytokines such as IL-10, IL-13, and IL-1-RA that would reduce chronic inflammation observed in nonhealing wounds. 44 Interestingly, we observed that adherent BM-dMSC and ASC secrete GM-CSF which is likely to have significant patient benefit for chronic wounds when applied locally.…”

Effects of intra-articular injection of mesenchymal stem cells associated with platelet-rich plasma in a rabbit model of osteoarthritis

“…The main mechanism of action for this regenerative behavior remains unclear. Cai et al (2007) suggested that this enhanced regenerative ability may be due to the secretory effects of the injected stem cells. Ong et al (2013) stated that enhanced regeneration may be due to direct engraftment and differentiation of stem cells that were introduced into the diseased joints; Pak et al (2016) postulated that it could be due the combination of secretory effects and direct engraftment of stem cells.…”