Jiahui Qi, Xiaoqiang Sheng, Shiyuan Li, Peipei Jiang, Huiyan Wang, Lingxi Li, Jidong Zhou, Yifan Li, Huidan Zhang, Miaomiao Wang, Yang Zhang, Guangfeng Zhao, Guijun Yan, Bruno Péault, Yali Hu, Haixiang Sun, Lijun Ding
Early uterine development in humans is a critical determinant of reproductive health and disease susceptibility during adolescence. While single-cell analyses have extensively characterized the adult uterus, the developmental origins of this organ remain poorly understood. In this study, single-cell RNA sequencing and spatial transcriptomics of the human uterus from gestational week 12 (GW12) to GW24 and from adolescents revealed a population of hyaluronan-mediated motility receptor-expressing (HMMR+) stromal cells essential for uterine endometrial and myometrial development. These HMMR+ stromal cells were highly proliferative and differentiated into stromal- and muscle-like lineages upon in vitro induction. Following xenotransplantation into immunodeficient mice, they engrafted and formed mesenchymal-like tissue expressing both stromal and smooth muscle markers. We determined that HMMR+ stromal cells promote epithelial cell differentiation and development through pleiotrophin signaling. Notably, these HMMR+ stromal cells were significantly reduced in the thin endometrium. Collectively, our findings define the cellular ontogeny of the human uterus and identify a pivotal stromal progenitor-like population with implications for developmental disorders and endometrial pathologies.