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

脂肪组织对缺氧的适应性变化：细胞死亡介导的干细胞激活

基本信息

批准号：
22659320
负责人：
YOSHIMURA Kotaro
金额：
$ 2.04万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Challenging Exploratory Research
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2011
项目状态：
已结题

项目摘要

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.

基于对损伤脂肪组织渗出液的分析，我们制备了一种含有与渗出液相同比例的损伤相关生长因子的混合物，称为脂肪损伤鸡尾酒（AIC）。我们假设AIC诱导了一系列再生和血管生成过程，而没有实际的创伤。本研究的目的是阐明AIC的治疗潜力。与血管内皮细胞相比，AIC优先激活脂肪源性干/祖细胞（ASC）增殖、迁移和形成毛细血管网络，而VEGF在hASC中不诱导有丝分裂或趋化性。AIC的每种生长因子对ASC的激活作用不同。AIC处理的ASCs倾向于分化为脂肪细胞或血管构成细胞，而不是其他细胞类型。在手术干预或糖尿病诱导的小鼠缺血性脂肪组织中，AIC给药增强了增殖，尤其是CD 31-/CD 34 + ASC的增殖，并通过增加毛细血管密度和减少纤维化来缓解组织缺氧。这些结果表明，AIC可能通过激活ASCs和其他细胞诱导脂肪重塑和新生血管形成，对各种缺血/缺氧条件具有治疗潜力。用AIC治疗在发病率、成本和物理风险方面具有优于基于细胞的疗法的许多优点，并且可以用于改善组织氧张力的替代疗法。