HMMR⁺ stromal cells drive human uterine development

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.