By creating the first transgenic mouse model of menstruation and revealing that tissue shedding is determined by a radial decidualization gradient, this work overturns a century-old endometrial model and unlocks mechanistic access to menstrual disorders.
Transgenic mice engineered for chemogenetic control of endometrial calcium or cAMP signaling recapitulate the anatomical, functional, and transcriptional hallmarks of human menstruation, including hormone-dependent vaginal bleeding, selective shedding of a superficial decidualized layer with preservation of a basal regenerative layer, and conservation of 31% of key decidualization-associated genes, while revealing that endometrial compartmentalization arises through a radial pattern of fibroblast differentiation that creates multilayered tissue organization beyond the classical functionalis-basalis dichotomy.
During menstruation, an inner layer of the endometrium is selectively shed, while an outer, progenitor-containing layer is preserved to support repeated regeneration. Progress in understanding this compartmentalization has been hindered by the lack of suitable animal models, as mice and rats do not menstruate. Here, we present transgenic mouse models that recapitulate the key anatomical, functional, and transcriptional features of human menstruation through targeted chemogenetic activation of premenstrual differentiation. Using single-cell spatial transcriptomics, we define a new paradigm for spatially regulated fibroblast differentiation that drives pre-menstrual endometrial layering and ultimately determines the extent of tissue shedding. Our results revise a century-old view of endometrial shedding and regeneration and establish new transgenic mice as powerful tools to advance menstruation research.