Macrophages are a key and heterogeneous cell population involved in endometrial repair and regeneration during the menstrual cycle, but their role in the development of intrauterine adhesion (IUA) and sequential endometrial fibrosis remains unclear. Here, we reported that CD301⁺ macrophages were significantly increased and showed their most active interaction with profibrotic cells in the endometria of IUA patients compared with the normal endometria by single-cell RNA sequencing, bulk RNA sequencing, and experimental verification. Increasing CD301⁺ macrophages promoted the differentiation of endometrial stromal cells into myofibroblasts and resulted in extracellular matrix accumulation, which destroyed the physiological architecture of endometrial tissue, drove endometrial fibrosis, and ultimately led to female infertility or adverse pregnancy outcomes. Mechanistically, CD301⁺ macrophages secreted GAS6 to activate the AXL/NF-κB pathway, upregulating the profibrotic protein synthesis. Targeted deletion of CD301⁺ macrophages or inhibition of AXL by Bemcentinib blunted the pathology and improved the outcomes of pregnancy in mice, supporting the therapeutic potential of targeting CD301⁺ macrophages for treating endometrial fibrosis.

中文翻译：

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靶向 CD301+ 巨噬细胞抑制子宫内膜纤维化并改善妊娠结局

巨噬细胞是参与月经周期子宫内膜修复和再生的关键异质细胞群，但它们在子宫内膜粘连（IUA）和继发性子宫内膜纤维化发展中的作用仍不清楚。在这里，我们通过单细胞 RNA 测序、批量 RNA 测序和实验验证发现，与正常子宫内膜相比，IUA 患者子宫内膜中 CD301 + 巨噬细胞显着增加，并显示出与促纤维化细胞最活跃的相互作用^。CD301 ⁺巨噬细胞的增加促进子宫内膜间质细胞分化为肌成纤维细胞并导致细胞外基质堆积，破坏子宫内膜组织的生理结构，驱动子宫内膜纤维化，最终导致女性不孕或不良妊娠结局。从机制上讲，CD301 ⁺巨噬细胞分泌 GAS6 激活 AXL/NF-κB 通路，上调促纤维化蛋白的合成。Bemcentinib靶向删除 CD301 ⁺巨噬细胞或抑制 AXL 可以削弱小鼠的病理学并改善妊娠结局，支持靶向 CD301 ⁺巨噬细胞治疗子宫内膜纤维化的治疗潜力。