Targeting endometrial inflammation in intrauterine adhesion ameliorates endometrial fibrosis by priming MSCs to secrete C1INH

• Published in: iScience Vol. 26; no. 7; p. 107201
• Main Authors: Yao, Simin, Zhou, Zhenhua, Wang, Limin, Lv, Haining, Liu, Dan, Zhu, Qi, Zhang, Xiwen, Zhao, Guangfeng, Hu, Yali
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21-07-2023; Elsevier
• Subjects: Cell biology; Fibrosis; Histology; Immunology; Sequence analysis; Cell biology; Histology; Immunology; Sequence analysis; Fibrosis
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.107201

Intrauterine adhesion (IUA) is a common cause of uterine infertility and its histopathologic characteristic is endometrial fibrosis. A shortage of stem cells in the endometrial basalis has been recognized as a common cause of IUA development because approximately 90% of patients suffer from IUA after endometrial injury. In this study, we provide evidence that persistent inflammation is the main contributor to endometrial fibrosis in IUA patients. We further found that treating an IUA-like mouse model with ITI-hUC-MSCs (hUC-MSCs reprogrammed by IL-1β, TNF-α and IFN-γ) significantly decreased endometrial inflammation and fibrosis. Mechanistically, high levels of complement 1 inhibitor (C1INH) secreted by ITI-hUC-MSCs prevented inflammation from inducing profibrotic CD301+ macrophage polarization by downregulating the JAK-STAT signaling pathway. In conclusion, persistent inflammation in the endometria of IUA patients provides macrophage polarization with a profibrotic niche to promote endometrial fibrosis, and the powerful immunomodulatory effects of ITI-hUC-MSCs improve the immune microenvironment of endometrial regeneration.
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•Persistent inflammation coexists with fibrosis in the endometria of IUA patients•Endometrial inflammation and its induction of CD301+ macrophages drive fibrosis•ITI-hUC-MSCs decrease endometrial inflammation and CD301+ macrophages in IUA mice•C1INH mediates ITI-hUC-MSCs’ anti-inflammation to improve endometrial fibrosis
Histology; Fibrosis; Immunology; Cell biology; Sequence analysis