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

Simin Yao; Zhenhua Zhou; Limin Wang; Haining Lv; Dan Liu; Qi Zhu; Xiwen Zhang; Guangfeng Zhao; Yali Hu

doi:10.1016/j.isci.2023.107201

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

iScience. 2023 Jun 24;26(7):107201. doi: 10.1016/j.isci.2023.107201. eCollection 2023 Jul 21.

Authors

Simin Yao¹, Zhenhua Zhou¹, Limin Wang¹, Haining Lv¹, Dan Liu¹, Qi Zhu¹, Xiwen Zhang¹, Guangfeng Zhao¹, Yali Hu¹

Affiliation

¹ Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.

Abstract

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.

Keywords: Cell biology; Fibrosis; Histology; Immunology; Sequence analysis.