Rizo Jason A, Ahmad Vakil, Pru Jacob M, Winuthayanon Sarayut, Challa Sridevi, Kim Tae Hoon, Jeong Jae-Wook, Spencer Thomas E, Kelleher Andrew M
Division of Animal Sciences, University of Missouri, Columbia, MO 65211.
Department of Obstetrics, Gynecology, and Women's Health, University of Missouri, Columbia, MO 65211.
Proc Natl Acad Sci U S A. 2025 Feb 4;122(5):e2422694122. doi: 10.1073/pnas.2422694122. Epub 2025 Jan 30.
Understanding how epithelial cells in the female reproductive tract (FRT) differentiate is crucial for reproductive health, yet the underlying mechanisms remain poorly defined. At birth, FRT epithelium is highly malleable, allowing differentiation into various epithelial types, but the regulatory pathways guiding these early cell fate decisions are unclear. Here, we use neonatal mouse endometrial organoids and assembloid coculture models to investigate how innate cellular plasticity and external mesenchymal signals influence epithelial differentiation. Our findings demonstrate that uterine epithelium undergoes marked age-dependent changes, transitioning from a highly plastic state capable of forming both monolayered and multilayered structures to a more restricted fate as development progresses. Interestingly, parallels emerge between the developmental plasticity of neonatal uterine epithelium and pathological conditions such as endometrial cancer, where similar regulatory mechanisms may reactivate, driving abnormal epithelial differentiation and tumorigenesis. These results not only deepen our understanding of early uterine development but also offer a valuable model for studying the progression of reproductive diseases and cancers.
了解女性生殖道（FRT）中的上皮细胞如何分化对于生殖健康至关重要，但其潜在机制仍不清楚。出生时，FRT上皮具有高度可塑性，能够分化为各种上皮类型，但指导这些早期细胞命运决定的调控途径尚不清楚。在这里，我们使用新生小鼠子宫内膜类器官和组装体共培养模型来研究先天细胞可塑性和外部间充质信号如何影响上皮分化。我们的研究结果表明，子宫上皮会发生明显的年龄依赖性变化，随着发育的进行，从能够形成单层和多层结构的高度可塑性状态转变为更受限的命运。有趣的是，新生子宫上皮的发育可塑性与子宫内膜癌等病理状况之间出现了相似之处，在这些病理状况中，类似的调控机制可能会重新激活，驱动异常的上皮分化和肿瘤发生。这些结果不仅加深了我们对早期子宫发育的理解，也为研究生殖疾病和癌症的进展提供了有价值的模型。
