间充质干细胞在高脂诱导肥胖发病中的作用及机制

Obesity is an energy-rich condition, which is always characterized by chronic and inflammatory responses in adipose tissue and liver, however, the potenial mechanism is unclear. Adipose tissue has plenty of mesenchymal stem cells (MSCs), the cells derived from it, besides the ability to differentiate into multiple types of cells, can also possess immunoregulatory roles. In our studies, we found that adipose derived MSCs from high fat-diet induced obesity mice showed enhanced CCL2 and ICAM-1 expression, compared with that of adipose derived MSCs from normal diet mice. In turn, the high levels of TNF-α in obesity can further promote the expressions of ICAM-1 and CCL2 in MSCs. Moreover, the expression of stearoyl-CoA desaturase 1 (SCD1) in MSCs derived from obesity mice was up-regulated which is correlated with adipogenesis and obesity, meanwhile, MSCs with TNF-α stimulation showed enhanced expression of SCD1. Until now, less research about the roles of MSCs in obesity development is reported. Based on the well-established high-fat induced obesity mouse model and the platform of MSCs, from multiple angles and multiple layers, studies will be performed to investigate how adipose derived MSCs from obesity mice regulate macrophage accumulation in adipose tissues and to explore how the inflammatory environments affect the functions of MSCs. Our studies will help us to expand our recognition about the regulatory roles of MSCs in obesity pathogenesis, and provide the theoretic and experimental evidences to better understand and treatment obesity.

肥胖与脂类代谢异常密切相关，是主要累及脂肪组织和肝脏的慢性炎症性疾病，其具体机制尚不清楚。脂肪组织拥有丰富的间充质干细胞（MSCs），它来源的MSCs除了具有分化为其它细胞（如脂肪细胞等）的潜能外，还具有免疫调节功能。我们发现，肥胖小鼠脂肪来源的MSCs，与对照组相比，所表达的ICAM-1和巨噬细胞趋化因子-CCL2明显升高。而肥胖发生时，脂肪组织形成的炎症环境如TNF-α的分泌可以进一步上调CCL2和ICAM-1在MSCs上的表达，同时与脂肪合成相关的基因-硬脂酰辅酶A脱氢酶1的表达也明显上调。迄今为止，关于MSCs在肥胖发病中的作用尚无报道。我们将利用已建立的肥胖小鼠模型以及脂肪来源的MSCs平台，多层次、多角度地研究肥胖小鼠脂肪来源的MSCs对于巨噬细胞的影响，并探讨肥胖小鼠脂肪部位炎症环境对于MSCs功能的影响，拓展我们对于肥胖发病机制的认识，为更好地治疗和预防肥胖提供了理论指导。

肥胖之于胰岛素抵抗、II型糖尿病正如吸烟之于肺癌，已经成为严重危害人类健康的重要因素。肥胖是一个慢性的炎症过程，其中，脂肪组织中以巨噬细胞为主的免疫细胞浸润是这种慢性炎症的一个重要体现。这些炎症细胞及其分泌的炎症因子是包括胰岛素抵抗，糖尿病在内的众多代谢疾病的直接因素。作为炎症反应的重要参与者，巨噬细胞在肥胖相关的炎症的发生和发展中发挥中枢作用。本项目利用已建立的高脂诱导肥胖的小鼠模型以及脂肪来源的间充质干细胞（mesenchymal stem cells，MSCs）平台，从多层次、多角度，研究肥胖小鼠脂肪来源MSCs对于巨噬细胞的影响，同时探讨肥胖小鼠脂肪部位炎症环境对于MSCs功能的影响，拓展我们对于MSCs在肥胖病理过程中调节作用的认识，为更好地认识与治疗肥胖提供理论和实验依据。研究发现，1）无论是高脂诱导肥胖，还是遗传性肥胖，脂肪组织中巨噬细胞的积聚增多依赖于肥胖早期脂肪组织内在巨噬细胞增殖和晚期单核细胞迁移的动态调控；2）肥胖脂肪组织中巨噬细胞的增殖依赖于IL-4/STAT6调控，单核细胞迁移依赖于脂肪MSCs分泌的高水平的CCL2；3）炎症因子刺激脂肪MSCs更易分化为脂肪细胞，促进脂肪组织的病理性重塑。体内及体外实验均证明，当MSCs中SHP1缺失后，MSCs成脂分化明显增强。构建了SHP1fl/flDermo1-cre小鼠，研究明确SHP-1在间质细胞中的缺失显著提高小鼠脂肪组织的体积。综上所述，本项目阐述了肥胖脂肪组织中巨噬细胞积聚的形成机制，发现MSCs参与构建脂肪组织巨噬细胞浸润的炎症环境，招募更多的巨噬细胞达到脂肪组织，而炎症细胞的到达进一步推动了有利于脂肪形成的基因的表达，形成正反馈，不断地促进肥胖进展。本项目的研究拓展了我们对肥胖发病机制的认识，为深入了解MSCs在肥胖的进展中的作用提供新的思路和途径，也为肥胖及相关疾病的临床治疗提供有价值的新靶标。