EXPERIMENTAL Adipose Tissue Remodeling under Ischemia: Death of Adipocytes and Activation of Stem/ Progenitor Cells Hirotaka Suga, M.D. Hitomi Eto, M.D. Noriyuki Aoi, M.D. Harunosuke Kato, M.D. Jun Araki, M.D. Kentaro Doi, M.D. Takuya Higashino, M.D. Kotaro Yoshimura, M.D. Tokyo, Japan Background: Following various types of plastic surgery, such as adipose grafting and flap elevation, adipose tissue undergoes ischemia, leading to hypoxia and nutrient depletion. However, few studies have examined ischemic and/or hy- poxic changes in adipose tissue. Methods: The authors established surgically induced ischemia models by sev- ering blood vessels supplying the inguinal fat pads in mice. The partial pressure of oxygen in adipose tissue was measured with an oxygen monitor, and ischemic changes were analyzed by whole-mount staining, immunohistochemistry, flow cytometry, and Western blotting. The authors also examined cell survival under a hypoxic condition in vitro. Results: Models for three degrees (mild, intermediate, and severe) of ischemia showed approximately 75, 55, and 20 percent of the partial pressure of oxygen level in normal adipose tissue (50.5  1.3 mm Hg), respectively. Adipose tissue atrophy with substantial fibrosis on day 28 was seen, depending on the severity of ischemia. Intermediate and severe ischemia induced elevated expression of hypoxia-inducible factor 1 and fibroblast growth factor 2 on day 1 and de- generative changes (i.e., apoptosis, necrosis, and macrophage infiltration and phagocytosis) in adipose tissue. Dead cells included adipocytes, vascular endo- thelial cells, and blood-derived cells, but not adipose-derived stem/progenitor cells. Subsequent to degenerative changes, regenerative changes were seen, including angiogenesis, adipogenesis, and proliferation of cells (adipose-de- rived stem/progenitor cells, vascular endothelial cells, and blood cells). The authors found that, in vitro, the experimentally differentiated adipocytes un- derwent apoptosis and/or necrosis under severe hypoxia, but adipose-derived stem/progenitor cells remained viable. Conclusions: Severe ischemia/hypoxia induces degenerative changes in adi- pose tissue and subsequent adaptive tissue remodeling. Adipocytes die easily under ischemic conditions, whereas adipose-derived stem/progenitor cells are activated and contribute to adipose tissue repair. (Plast. Reconstr. Surg. 126: 1911, 2010.) V arious types of plastic surgery, such as fat grafting and flap elevation, result in isch- emia and hypoxia of adipose tissue. Vascu- larization and oxygenation of adipose tissue strongly impact clinical outcomes, such as the long-term volume of reconstructed tissue. Adipose tissue easily degenerates on ischemia, and a sig- nificant portion is absorbed after free grafting. 1–4 However, most studies have examined ischemic changes in adipose tissue histologically rather than at the cellular and molecular levels. In ad- dition, it is unclear what degree of ischemia or hypoxia induces histologic changes and/or irre- versible tissue atrophy in adipose tissue. Adipose tissue is composed of both adipocytes and other cell types, such as adipose stem/pro- genitor/stromal cells and vascular endothelial From the Department of Plastic Surgery, University of Tokyo School of Medicine. Received for publication January 18, 2010; accepted May 25, 2010. Copyright ©2010 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0b013e3181f4468b Disclosure: The authors have no conflicts of inter- est to disclose. www.PRSJournal.com 1911