Adaptive changes of adipose tissue to hypoxia : cell death-mediated activation of stem cells

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Based on the analysis of exudates from injured adipose tissue, we prepared a mixture containing the injury-associated growth factors at the same proportion as the exudates, named adipose injury cocktail(AIC). We hypothesized that AIC induces a series of regenerating and angiogenic processes without actual wounding. The purpose of this study is to elucidate therapeutic potentials of AIC. AIC preferentially activated adipose-derived stem/progenitor cells(ASCs) to proliferate, migrate, and form capillary networks compared to vascular endothelial cells, while VEGF did not induce mitogenesis or chemotaxis in hASCs. Each component growth factor of AIC was differently responsible for the ASC activation. AIC-treated ASCs tended to differentiate into adipocytes or vessel-constituting cells rather than other cell types. In ischemic adipose tissues of mice, induced either by a surgical intervention or by diabetes, AIC administration enhanced proliferation, especially of CD31-/CD34+ASCs, and mitigated tissue hypoxia by increasing capillary density and reducing fibrogenesis. These results suggested that AIC may have therapeutic potentials for various ischemic/hypoxic conditions by inducing adipose remodeling and neovascularization through activation of ASCs and other cells. Treatment with AIC has many advantages over cell-based therapies with regard to morbidity, cost, and physical risks, and may be used for an alternative therapy for improving tissue oxygen tension.