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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Numerous reports showed that the epididymis plays key roles in the acquisition of sperm fertilizing ability but its contribution to embryo development remains less understood. Female mice mated with males with simultaneous mutations in Crisp1 and Crisp3 genes exhibited normal in vivo fertilization but impaired embryo development. In this work, we found that this phenotype was not due to delayed fertilization, and it was observed in eggs fertilized by epididymal sperm either in vivo or in vitro. Of note, eggs fertilized in vitro by mutant sperm displayed impaired meiotic resumption unrelated to Ca2+ oscillations defects during egg activation, supporting potential sperm DNA defects. Interestingly, cauda but not caput epididymal mutant sperm exhibited increased DNA fragmentation, revealing that DNA integrity defects appear during epididymal transit. Moreover, exposing control sperm to mutant epididymal fluid or to Ca2+-supplemented control fluid significantly increased DNA fragmentation. This, together with the higher intracellular Ca2+ levels detected in mutant sperm, supports a dysregulation in Ca2+ homeostasis within the epididymis and sperm as the main factor responsible for embryo development failure. These findings highlight the contribution of the epididymis beyond fertilization and identify CRISP1 and CRISP3 as novel factors essential for sperm DNA integrity and early embryo development.
