M1/M2型巨噬细胞在PDGFRα阳性前体脂肪细胞成脂分化中的作用及其机制研究

Adipogenesis is one of the most important research projects in the field of fat grafting. It is now believed that the newly generated adipocytes were mainly derived from the adipogenic differentiation of PDGFRα+ preadipocytes. However, the regulatory mechanisms of the adipocyte differentiation in an in vivo microenvironment are still not clear. Recent studies suggested that adipose tissue macrophages (ATMs) have close relationship with adipogenesis, but whether macrophages play a promotive or inhibitory role is still controversial. Researchers have found that macrophages infiltration into fat grafts exhibits two different phenotypes: the main subsets of macrophages at an early stage are pro-inflammatory M1 macrophages; however, the main subsets of macrophages at a later stage are anti-inflammatory and pro-tissue remodeling M2 macrophages. Because of their functional differences, we hypothesize that M1 macrophages and M2 macrophages may have different effect on the adipogenic differentiation of preadipocytes. To investigate the role of different macrophage subsets (M1 and M2) during adipocyte differentiation, a methodology for selective depletion of M1 macrophages or M2 macrophages will be adopted in this project. We will also examine the activation of canonical Wnt signaling (critical for the control of adipogenesis) in preadipocytes, to get a further analysis of the role and mechanism of M1 and M2 macrophages during adipogenic differentiation of PDGFRα+ preadipocytes.

脂肪细胞再生是脂肪移植领域的重要研究课题。目前认为新生脂肪细胞主要来自PDGFRα+前体脂肪细胞的成脂分化，然而体内微环境对这一过程的调控机制仍不十分清楚。最近研究提示，脂肪组织内的巨噬细胞与前体脂肪细胞的成脂分化有极其密切的关系，但其对成脂分化的调控作用是促进还是抑制却存在很大争议。现已发现脂肪移植物内的巨噬细胞浸润包含两种不同亚型，早期以促进炎症反应的M1型为主，后期以抗炎及促进组织修复的M2型为主。我们推测M1/M2型巨噬细胞因其功能上的差异可能对前体脂肪细胞的成脂分化产生截然不同的作用。本研究拟通过选择性清除M1型或M2型巨噬细胞的实验方法，探讨M1/M2型巨噬细胞对PDGFRα+前体脂肪细胞体外和体内成脂分化能力的影响；同时，通过检测前体脂肪细胞内成脂分化关键信号途径“经典Wnt信号通路”的活化状态，进一步明确M1/M2型巨噬细胞在前体脂肪细胞成脂分化中的作用及其调控机制。

脂肪细胞再生是脂肪移植领域的重要研究课题。脂肪组织内巨噬细胞与前体脂肪细胞的成脂分化有极其密切的关系，但其对成脂分化的调控作用是促进还是抑制却存在很大争议。本研究明确了脂肪移植早期阶段巨噬细胞M1型向M2型的极化。体外实验结果显示M1型巨噬细胞明显抑制PDGFRα+前体脂肪细胞成脂分化，而M2型巨噬细胞并没有表现出对PDGFRα+前体脂肪细胞成脂的促进或抑制作用。体内实验结果显示M1型巨噬细胞对脂肪移植物内的成脂表达（PPARγ和C/EBPα）有明显的抑制作用，而M2型巨噬细胞对脂肪移植物内的成脂表达（PPARγ和C/EBPα）无明显影响。本研究结果揭示了炎症微环境中M1型巨噬细胞对脂肪移植后脂肪细胞再生的抑制作用，为进一步研究在脂肪移植早期阶段加速M1型巨噬细胞向M2型巨噬细胞极化，能否促进脂肪移植物内的脂肪细胞再生，提供了依据。