Single-cell sequencing of neonatal uterus reveals an endometrial progenitor indispensable for fertility
- Massachusetts General Hospital, United States
- Harvard Medical School, United States
- University of Massachusetts, United States
Abstract
The Mullerian ducts are the anlagen of the female reproductive tract, which regress in the male fetus in response to MIS. This process is driven by subluminal mesenchymal cells expressing Misr2, which trigger the regression of the adjacent Mullerian ductal epithelium. In females these Misr2+ cells are retained, yet their contribution to the development of the uterus remains unknown. Here, we report that subluminal Misr2+ cells persist postnatally in the uterus of rodents, but recede by week 37 of gestation in humans. Using single-cell RNA sequencing we demonstrate that ectopic postnatal MIS administration inhibits these cells and prevents the formation of endometrial stroma in rodents, suggesting a progenitor function. Exposure to MIS during the first six days of life, by inhibiting specification of the stroma, dysregulates paracrine signals necessary for uterine development, eventually resulting in apoptosis of the Misr2+ cells, uterine hypoplasia, and complete infertility in the adult female.
Data availability
Sequencing data have been deposited in OSF platform, the link is as follows:https://osf.io/27hej/?view_only=23f651c1523b4653a250780767160db7
Article and author information
Author details
Hatice Duygu Saatcioglu
Funding
Michelson Prize and Grants (MG14-S06R)
- Patricia K Donahoe
- David Pépin
Huiying Fellowship
- Hatice Duygu Saatcioglu
Sudna Gar Fellowship
- David Pépin
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in accordance with experimental protocols 2009N000033 and 2014N000275 approved by the Massachusetts General Hospital Institutional Animal Care and Use Committee
Human subjects: Human fetal tissue sections were procured by the Massachusetts General Hospital, Gynecological Pathology Department through The Institutional Review Board (IRB) approved protocol (#IRB 2007P001918).
Copyright
© 2019, Saatcioglu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Single-cell sequencing of neonatal uterus reveals an endometrial progenitor indispensable for fertility
eLife 8:e46349.
https://doi.org/10.7554/eLife.46349
Further reading
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- Cell Biology
- Developmental Biology
Long thought to have little relevance to ovarian physiology, the rete ovarii may have a role in follicular dynamics and reproductive health.
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- Cell Biology
- Developmental Biology
The rete ovarii (RO) is an appendage of the ovary that has been given little attention. Although the RO appears in drawings of the ovary in early versions of Gray’s Anatomy, it disappeared from recent textbooks, and is often dismissed as a functionless vestige in the adult ovary. Using PAX8 immunostaining and confocal microscopy, we characterized the fetal development of the RO in the context of the mouse ovary. The RO consists of three distinct regions that persist in adult life, the intraovarian rete (IOR), the extraovarian rete (EOR), and the connecting rete (CR). While the cells of the IOR appear to form solid cords within the ovary, the EOR rapidly develops into a convoluted tubular epithelium ending in a distal dilated tip. Cells of the EOR are ciliated and exhibit cellular trafficking capabilities. The CR, connecting the EOR to the IOR, gradually acquires tubular epithelial characteristics by birth. Using microinjections into the distal dilated tip of the EOR, we found that luminal contents flow toward the ovary. Mass spectrometry revealed that the EOR lumen contains secreted proteins potentially important for ovarian function. We show that the cells of the EOR are closely associated with vasculature and macrophages, and are contacted by neuronal projections, consistent with a role as a sensory appendage of the ovary. The direct proximity of the RO to the ovary and its integration with the extraovarian landscape suggest that it plays an important role in ovary development and homeostasis.
