Adipose Injury–Associated Factors Mitigate Hypoxia in Ischemic Tissues through Activation of Adipose-Derived Stem/Progenitor/Stromal Cells and Induction of Angiogenesis

Abstract

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 the therapeutic potentials of AIC. AIC preferentially activated adipose-derived stem/progenitor/stromal cells (ASCs) to proliferate, migrate, and form networks compared with vascular endothelial cells, whereas vascular endothelial growth factor did not induce mitogenesis or chemotaxis in human ASCs. 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 into other cell types. In ischemic adipose tissues of mice, induced by either a surgical intervention or diabetes, AIC administration enhanced proliferation, especially of CD31 -/CD34 ؉ ASCs, and mitigated tissue hypoxia by increasing capillary density and reducing fibrogenesis. These results suggest 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 regarding morbidity, cost, and physical risks and may be used as an alternative therapy for improving tissue oxygen.

Human Adipose-Derived Cells: An Update on the Transition to Clinical Translation

“…This effect has been attributed to their secretion of angiogenic factors [45]. Additional studies have determined that ASCs exposed to ischemia or hypoxia secrete cytokines that can improve cell proliferation and vasculogenesis directly, without the presence of the ASCs themselves [78]. Exposure of ASCs to these hypoxia-induced cytokines promotes their differentiation along the adipocyte and endothelial pathways [78].…”

“…Additional studies have determined that ASCs exposed to ischemia or hypoxia secrete cytokines that can improve cell proliferation and vasculogenesis directly, without the presence of the ASCs themselves [78]. Exposure of ASCs to these hypoxia-induced cytokines promotes their differentiation along the adipocyte and endothelial pathways [78]. This suggests that ASC-conditioned medium alone may be sufficient to treat ischemic injuries without the need for direct cell transplantation [78].…”

The Fate of Adipocytes after Nonvascularized Fat Grafting

“…10,11 We previously reported the orchestrated cell interactions caused by manipulations of adipose tissue such as mechanical injury, ischemia-reperfusion injury, and surgically induced ischemia. [12][13][14][15] In these studies, adipose stem/stromal/progenitor cells (adipose-derived stromal cells) were shown to play pivotal roles in adipose tissue repair/remodeling; they increase in number, contribute to angiogenesis/adipogenesis in response to primary signals released from the injured tissue, and release various secondary growth factors. 16,17 However, adipose tissue survival/remodeling after nonvascularized fat grafting should differ from that after both mechanical injury and ischemia (partly corresponding to vascularized transposition of the adipose flap) and that after ischemia-reperfusion injury (corresponding to a revascularized free flap with a microsurgical anastomosis).…”

Generation of Skin Tissue Using Adipose Tissue-Derived Stem Cells

“…Adipose tissue-derived mesenchymal stem cells accelerate neoangiogenesis and exert an antioxidant effect. 28,29 The different survival rate of, and epidermis formation by, keratinocytes in group 5 compared to those in group 3 was likely attributable to them being less exposed to rapid neoangiogenesis and ischemia. Green fluorescent protein-expressing mesenchymal stem cells originating from fat tissue displayed epithelial differentiation 4 weeks after application, as determined by staining with cytokeratin-19.…”