Uterine organoids reveal insights into epithelial specification and plasticity in development and disease
Contributed by Thomas E. Spencer; received November 11, 2024; accepted December 26, 2024; reviewed by Richard R. Behringer, Paul S. Cooke, and Pradeep S. Tanwar
Significance
These studies reveal pronounced age-dependent epithelial plasticity in the uterus, driven by intrinsic cellular properties and mesenchymal crosstalk. Using mouse genetic models, neonatal endometrial organoids, and assembloids, we uncover parallels between normal epithelial differentiation and pathological states, highlighting conserved pathways that govern uterine epithelial fate decisions. These findings provide insights into the developmental plasticity of the uterine epithelium and underscore the essential role of epithelial–stromal interactions in regulating uterine development and disease progression.
Abstract
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.
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Data, Materials, and Software Availability
RNA-seq data have been deposited in NCBI Gene Expression Omnibus (GSE278635) (110). All study data are included in the article and/or supporting information.
Acknowledgments
We would like to thank members of the Spencer and Kelleher laboratory for helpful discussions, the Jeong and Kim laboratory for mouse model generation, Dr. Anh Quynh Nguyen for endometrial cancer organoid generation, the Genomics Technology Core and the Charles W. Gehrke Proteomics Center at the University of Missouri-Columbia, and the University of Chicago Organoid and Primary Culture Research Core. This work was supported by NIH Grant R01HD112315 (A.M.K.), NIH Grant 1R37HD114609 (T.E.S. and A.M.K.), the Paula and Rodger Riney Foundation (A.M.K. and T.H.K.), the National Center for Advancing Translational Sciences (NCATS) through NIH Grant UL1TR002389-07 that funds the Institute for Translational Medicine (ITM) at the University of Chicago (S.C.).
Author contributions
J.A.R., T.E.S., and A.M.K. designed research; J.A.R., V.A., and J.M.P. performed research; S.C., T.H.K., and J.-W.J. contributed new reagents/analytic tools; J.A.R., S.W., T.E.S., and A.M.K. analyzed data; and J.A.R., T.E.S., and A.M.K. wrote the paper.
Competing interests
The authors declare no competing interest.
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Copyright © 2025 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Data, Materials, and Software Availability
RNA-seq data have been deposited in NCBI Gene Expression Omnibus (GSE278635) (110). All study data are included in the article and/or supporting information.
Submission history
Received: November 11, 2024
Accepted: December 26, 2024
Published online: January 30, 2025
Published in issue: February 4, 2025
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Acknowledgments
We would like to thank members of the Spencer and Kelleher laboratory for helpful discussions, the Jeong and Kim laboratory for mouse model generation, Dr. Anh Quynh Nguyen for endometrial cancer organoid generation, the Genomics Technology Core and the Charles W. Gehrke Proteomics Center at the University of Missouri-Columbia, and the University of Chicago Organoid and Primary Culture Research Core. This work was supported by NIH Grant R01HD112315 (A.M.K.), NIH Grant 1R37HD114609 (T.E.S. and A.M.K.), the Paula and Rodger Riney Foundation (A.M.K. and T.H.K.), the National Center for Advancing Translational Sciences (NCATS) through NIH Grant UL1TR002389-07 that funds the Institute for Translational Medicine (ITM) at the University of Chicago (S.C.).
Author contributions
J.A.R., T.E.S., and A.M.K. designed research; J.A.R., V.A., and J.M.P. performed research; S.C., T.H.K., and J.-W.J. contributed new reagents/analytic tools; J.A.R., S.W., T.E.S., and A.M.K. analyzed data; and J.A.R., T.E.S., and A.M.K. wrote the paper.
Competing interests
The authors declare no competing interest.
Notes
Reviewers: R.R.B., Monroe Dunaway Anderson Cancer Center, The University of Texas; P.S.C., University of Florida; and P.S.T., The University of Newcastle.
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Uterine organoids reveal insights into epithelial specification and plasticity in development and disease, Proc. Natl. Acad. Sci. U.S.A.
122 (5) e2422694122,
https://doi.org/10.1073/pnas.2422694122
(2025).
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