Deciphering the endometrial niche of human thin endometrium at single-cell resolution

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 119; no. 8
• Main Authors: Lv, Haining, Zhao, Guangfeng, Jiang, Peipei, Wang, Huiyan, Wang, Zhiyin, Yao, Simin, Zhou, Zhenhua, Wang, Limin, Liu, Dan, Deng, Wenbo, Dai, Jianwu, Hu, Yali
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 22-02-2022
• Subjects: Abnormalities; Biological Sciences; Blood vessels; Carrier Proteins - metabolism; Cell cycle; Collagen; Cytokine TWEAK - metabolism; Cytokines - metabolism; Endometrium; Endometrium - metabolism; Endometrium - pathology; Endometrium - physiology; Epidermal Growth Factor - metabolism; Epithelial Cells - metabolism; Epithelium; Female; Gene Expression - genetics; Gene sequencing; Humans; Infertility; Infertility, Female - etiology; Infertility, Female - physiopathology; Macrophages; Natural killer cells; Pathogenesis; Regeneration; Semaphorin-3A - genetics; Semaphorin-3A - metabolism; Senescence; Signal transduction; Signal Transduction - genetics; Signaling; Single-Cell Analysis; Stromal cells; Stromal Cells - metabolism; Transcriptome - genetics; Transcriptomes; single-cell sequencing; cellular senescence; cell proliferation; thin endometrium
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2115912119

Thin endometrium has been widely recognized as a critical cause of infertility, recurrent pregnancy loss, and placental abnormalities; however, access to effective treatment is a formidable challenge due to the rudimentary understanding of the pathogenesis of thin endometrium. Here, we profiled the transcriptomes of human endometrial cells at single-cell resolution to characterize cell types, their communications, and the underlying mechanism of endometrial growth in normal and thin endometrium during the proliferative phase. Stromal cells were the most abundant cell type in the endometrium, with a subpopulation of proliferating stromal cells whose cell cycle signaling pathways were compromised in thin endometrium. Both single-cell RNA sequencing and experimental verification revealed cellular senescence in the stroma and epithelium accompanied by collagen overdeposition around blood vessels. Moreover, decreased numbers of macrophages and natural killer cells further exacerbated endometrial thinness. In addition, our results uncovered aberrant SEMA3, EGF, PTN, and TWEAK signaling pathways as causes for the insufficient proliferation of the endometrium. Together, these data provide insight into therapeutic strategies for endometrial regeneration and growth to treat thin endometrium.