A transient epithelial plasticity state defines the developmental window for uterine gland specification [Spatial]

ABSTRACT: Uterine gland development and function is essential for reproduction and women's health, yet the epithelial cell states and signaling interactions that govern gland fate specification are not well understood. Here, integration of single cell and spatial transcriptomics with organoid culture, lineage tracing, and genetic and hormonal perturbation models were used to define mechanisms regulating postnatal uterine epithelial differentiation. A developmentally restricted epithelial plasticity state was identified that precedes luminal and glandular cell lineage segregation and accompanied by dynamic reorganization of stromal-epithelial communication during uterine differentiation. Pseudotime analysis revealed progressive acquisition of gland-associated programs, including forkhead box A2 (Foxa2), retinoic acid metabolic genes, and epithelial estrogen receptor alpha (Esr1) expression. Functional studies revealed that ESR1 acquisition and retinoic acid signaling suppress the multilayered organoid phenotype associated with epithelial plasticity, thereby promoting epithelial specification and lineage commitment. Moreover, neonatal hormonal perturbation of adenogenesis and conditional deletion of Foxa2 abolished this organoid phenotype. Together, these findings establish neonatal uterine organoids as a valuable system for investigating mechanisms that regulate glandular epithelial cell fate specification during reproductive tract development.

ORGANISM(S): Mus musculus

PROVIDER: GSE331354 | GEO | 2026/08/10

REPOSITORIES: GEO