CD301+巨噬细胞亚群通过分泌GAS6促进子宫内膜纤维化的机制研究

宫腔粘连（IUA）的典型病理特征是子宫内膜纤维化。具有高度可塑性的巨噬细胞在启动组织纤维化过程中发挥重要作用，但哪类巨噬细胞在子宫内膜纤维化中起关键作用仍然不清。我们发现CD301+巨噬细胞亚群在IUA患者内膜中显著增加；体外实验证实CD301+巨噬细胞促进内膜间质细胞向肌成纤维细胞分化，且与其分泌的GAS6有关；我们还发现，IUA患者内膜中IL-34明显高表达，并促进单核/巨噬细胞向CD301+巨噬细胞分化。故我们假设：CD301+巨噬细胞是促进子宫内膜纤维化的关键细胞；内膜微环境中高表达的IL-34可诱导CD301+巨噬细胞数量及其GAS6分泌的增加，导致间质细胞向肌成纤维细胞分化，造成子宫内膜纤维化。本课题将明确IL-34对CD301+巨噬细胞分化的调控作用；揭示CD301+巨噬细胞及其分泌的GAS6促进内膜纤维化的机制；提出干预CD301+巨噬细胞/GAS6抑制内膜纤维化的新策略。

The typical pathologic feature of intrauterine adhesions (IUA) is endometrial fibrosis. Highly plastic macrophages play an important role in initiating tissue fibrosis, but it is not clear which type of macrophage plays a key role in endometrial fibrosis. We found that CD301 positive (CD301+) macrophage subset increased significantly in the endometrium of patients with IUA, and that CD301+ macrophages promoted the differentiation of endometrial stromal cells into myofibroblasts in vitro and was associated with GAS6 secreted by them. We also found that IL-34 was overexpressed in the endometrium of patients with IUA and promoted monocyte/ macrophage differentiation to CD301+ macrophages. Therefore, we hypothesized that CD301+ macrophages are the key cells to promote endometrial fibrosis, and that IL-34 overexpression in endometrial microenvironment can induce the increase of the number of CD301+ macrophages and the secretion of GAS6, and induce the differentiation of stromal cells into myofibroblasts, causing endometrial fibrosis. This study will clarify the role of IL-34 in regulating the differentiation of CD301+ macrophages, reveal the mechanism of CD301+ macrophages and GAS6 secreted by CD301+ macrophages in promoting endometrial fibrosis, and propose a new strategy to intervene CD301+ macrophages/GAS6 in inhibiting endometrial fibrosis.