Decoding the endometrial niche of Asherman’s Syndrome at single-cell resolution

Abstract

Infertility; Molecular medicine

Infertilidad; Medicina molecular

Infertilitat; Medicina molecular

Asherman’s Syndrome is characterized by intrauterine adhesions or scarring, which cause infertility, menstrual abnormalities, and recurrent pregnancy loss. The pathophysiology of this syndrome remains unknown, with treatment restricted to recurrent surgical removal of intrauterine scarring, which has limited success. Here, we decode the Asherman’s Syndrome endometrial cell niche by analyzing data from over 200,000 cells with single-cell RNA-sequencing in patients with this condition and through in vitro analyses of Asherman’s Syndrome patient-derived endometrial organoids. Our endometrial atlas highlights the loss of the endometrial epithelium, alterations to epithelial differentiation signaling pathways such as Wnt and Notch, and the appearance of characteristic epithelium expressing secretory leukocyte protease inhibitor during the window of implantation. We describe syndrome-associated alterations in cell-to-cell communication and gene expression profiles that support a dysfunctional pro-fibrotic, pro-inflammatory, and anti-angiogenic environment.

This study was jointly supported by Human Uterus Cell Atlas Project from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 874867, PROMETEO/2018/161 from the Valencia Government, IDI-20201142 CDTI from the Spanish Government and Carlos Simon Foundation, Spain. X.S. and E.F. were partially supported by IDI-20201142 CDTI from the Spanish Government. B.R. was supported by the H2020-funded project Human Uterus Cell Atlas (HUTER) (2020/2021) (Grant Agreement 874867). R.P. was supported by an Industrial Doctorate grant (DIN2020-011069) from the Spanish Ministry of Science and Innovation (MICINN). N.V. was supported by PROMETEO/2018/161. J.G.F. was supported by a PFIS grant [FI19/00159]. J.L. was supported by INVEST/2022/478 program. A.S. was supported by Estonian Research Council (PRG1076) and Horizon 2020 innovation grant (ERIN, grant no. EU952516). I.M. was supported by an FIS project grant [PI21/00235]. F.V. was supported by an FIS project grant [PI21/00528]. Other data that support the findings of this study are available from Asherman Therapy SL. Restrictions apply to data access with data used under license for the current clinical study and are not publicly available. Data are, however, available from the authors upon reasonable request and with permission of the Vall Hebron Ethical Committee.