血管周围脂肪干细胞在血管新生中的作用和分化机制

Obesity changes the distribution and secreting characteristic of adipose tissue, contributing to various cardiovascular diseases. Subcutaneous and abdominal adipose tissue contain adipose-derived stem cells (ASC) which can participate in angiogenesis. However, whether PVAT has perivascular ASC (PV-ASC) and whether PV-ASC can participate in angiogenesis are not identified. Our preliminary experiment confirmed the existence of PV-ASC in murine PVAT. We demonstrated that PV-ASC could differentiate into smooth muscle cells (SMC) and endothelial cells in vitro and expressed different characteristics from subcutaneous and abdominal ASC. Upon the differentiation from stem cells to SMC, lipid metabolism is enhanced. Carnitine Acetyltransferase (CRAT) is critical for lipid metabolism in mitochondria. We discovered that TGF-β1 could inhibit the activation of CRAT and enhance lipid metabolism, inducing the differentiation of PV-ASC to SMC; The application of PV-ASC in hindlimb ischemia mouse model significantly recovered blood flow. To sum up, we hypothesized that PV-ASC could differentiate into SMC in response to TGF-β1 via inhibiting CRAT-mediated pathway, subsequently participating in angiogenesis. Our study will elucidate the effect and differentiating mechanism of PV-ASC in angiogenesis, which can provide potential target for the regulation of angiogenesis.

肥胖改变体内脂肪的分布与分泌特性参与各类心血管疾病。皮下和腹腔脂肪组织含有脂肪干细胞（ASC）并参与血管新生，但血管周围脂肪（PVAT）是否含有干细胞及其作用尚未见报道。我们的初步研究证实小鼠PVAT存在脂肪干细胞（PV-ASC），可在体外被诱导分化为平滑肌（SMC）和内皮细胞，并具有不同于皮下和腹腔来源ASC的特征。干细胞向SMC分化过程中伴随脂代谢水平上调。肉碱乙酰转移酶（CRAT）是线粒体内脂质代谢的重要调控蛋白。我们的研究显示TGF-β1可抑制CRAT的表达，上调脂代谢水平从而促进PV-ASC向SMC分化；小鼠下肢缺血模型中发现PV-ASC显著改善血流灌注。据此推测：缺血等应激使TGF-β1等细胞因子释放，通过抑制CRAT酶介导的信号通路促进PV-ASC向SMC分化，参与血管新生。研究结果将首次阐明PV-ASC在血管新生中的作用和分化机制，为寻找新的干预靶点提供科学依据。

肥胖改变体内脂肪的分布与分泌特性参与各类心血管疾病。皮下和腹腔脂肪组织含有脂肪干细胞（ASC）并参与血管新生，但血管周围脂肪（PVAT）是否含有干细胞及其作用尚未见报道。此外，皮下和腹腔来源ASCs的异质性已被充分研究，但是PV-ASCs的异质性仍未见报道。我们应用了单细胞测序技术、体内及体外实验证实了PV-ASCs由Dpp4+,Col4a2+/Icam1+,Clec11a+/Cpe+和Sult1e1+四个亚群组成。其中Clec11a亚群与PV-ASCs分化为平滑肌细胞密切相关。利用同一单细胞数据库进行深度二次分析，发现MGP和TBX20是调控PV-ASCs分化为平滑肌细胞的关键分子。结合小鼠股动脉导丝拉伤模型，利用小分子抑制剂证实了调控MGP和TBX20在血管内膜增生性疾病的潜在临床价值。