CD146+子宫血管旁多能细胞表达SDF1抑制子宫内膜纤维化的机制研究

Severe scarring of the uterus is a difficult disease and the mechanism remains unclear. Along with the in-depth study, fibrosis and local stem cells lacking are cognitive. Although we have reported that stem cells transplantation for treatment of severe Asherman’s syndrome shows primarily effective outcomes, the mechanism of endometrial fibrosis in Asherman’s syndrome is still elusive. Recent fibrosis studies in other tissues have confirmed that CD146+ pericytes are major sources of myofibroblast, a key effector for organ fibrosis. Our primary results showed that endometrial pericytes with high multi-potency expressed CD146, NF-κB and SDF1. There are multiple putative NF-κB binding sites in SDF1’s promoter, which indicates that SDF1 may be an important target of CD146/NF-κB. After knock-down of SDF1, CD146+ pericytes differentiated toward myofibroblasts. We speculate that CD146/NF-κB/SDF1 pathway in endometrial pericytes plays a vital role in inhibition of differentiation of pericytes and regeneration of scarred endometrium. In the present study, we will analyze the molecular mechanism of SDF1 expression regulated by CD146 in endometrial pericytes for anti-fibrosis. During endometrial fibrosis, CD146+ cell tracing using genetic modified mouse will provide the evidence for origin of myofibroblasts. Furthermore, CBD-SDF1 injection for the treatment of uterus fibrosis will be carried out in the model rats that may lay the foundations for stem cell transplantation in the treatment of human uterine scar.

重度Asherman综合征是临床疑难疾病，治疗手段匮乏。近年来，其干细胞减少及纤维化的特征被认知，但子宫内膜纤维化的机制仍不清楚。多种组织纤维化的研究报道，CD146+血管旁细胞是纤维化效应细胞-肌成纤维细胞的主要来源。预实验结果显示，子宫内存在血管旁多能细胞，高表达CD146、NF-κB和趋化因子SDF1，具有分化为肌成纤维细胞的能力；我们通过生物信息学检索发现SDF1启动子区存在多个NF-κB潜在结合位点；体外敲低SDF1表达后，血管旁多能细胞分化为肌成纤维细胞。因此，我们推测CD146/NF-κB/SDF1通路在抑制血管旁多能细胞分化为肌成纤维细胞过程中起到关键作用。本研究中，我们将明确子宫血管旁多能细胞通过CD146/NF-κB调控SDF1的机制、体内分化为肌成纤维细胞的路径以及CBD-SDF1治疗模型大鼠子宫纤维化的效能，为人子宫内膜纤维化的机制阐明和治疗提供依据。

重度Asherman综合征患者子宫内膜干细胞减少、呈现纤维化改变，引起月经异常、不孕和流产，病理机制尚不明确，临床缺乏有效的治疗手段。本研究发现，我们前期鉴定的一类具有间充干细胞表型的子宫血管旁多能细胞在重度Asherman综合征患者子宫内膜中显著减少，其标志物CD146表达降低。为进一步示踪CD146+ PDGFRβ+血管旁多能细胞在子宫纤维化病变中的转分化路径，我们构建了CD146-LSL-tdTomato; PDGFRβ-cre基因工程小鼠，并在此基础上利用机械损伤联合LPS构建了子宫纤维化小鼠模型。基于子宫血管旁细胞的多能性与促血管生成能力，我们通过生物工程材料改良了细胞递送方式，利用水凝胶微针贴片/干细胞系统可有效恢复大鼠子宫损伤区域的组织形态、促进血管新生与肌层重建、增加子宫内膜容受性、改善生育能力。本课题为研究子宫纤维化病变的病理机制以及探讨子宫内膜血管旁多能细胞如何参与疾病病程提供了依据与研究方法，并为临床治疗重度Asherman综合征提供了新思路。