Segmental specification of the human female fetal reproductive tract revealed by spatiotemporal dynamics

The proper development of the human female reproductive tract (FRT) is essential for reproductive competence. However, the mechanisms underlying its segmental specialization remain underexplored. This gap limits our knowledge of congenital anomalies and adult reproductive disorders. Herein, we build a spatiotemporal transcriptomic atlas of the distinct human FRT segments development from gestational week (GW) 10 to 25, capturing cellular composition and lineage dynamics. We discovered that the upper and lower segments of FRT are composed of distinct mesenchymal and epithelial cell subpopulations starting from as early as GW10. Mesenchymal lineages in different segments arise from distinct mesenchymal stem cell (MSC)-like cells and undergo critical differentiation between GW13 and GW22, giving rise to fibroblasts and smooth muscle cells. TGF-β and PDGF signalling pathways seem to play a pivotal role in guiding these distinct fate transitions. Concurrently, epithelial development exhibits region-specific trajectories: upper and lower FRT epithelial cells originate from different stem-like populations and undergo key transitions between GW14 and GW22. Specifically, we identify MSC-like1 and MSC-like2 as regulatory populations that may influence epithelial differentiation via WNT5A-FZD and IGF1-IGF1R signalling pathways in the upper and lower FRT, respectively. This finding highlights a spatially specific mesenchymal-epithelial crosstalk that shapes regional epithelial identity. Altogether, our work provides a comprehensive insight into the segmental specification and coordinated lineage decisions that offer foundational resource for understanding FRT development, congenital anomalies and tissue engineering.