Single-cell sequencing of neonatal uterus reveals an endometrial progenitor indispensable for fertility

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

The following data sets were generated

Article and author information

Author details

  1. Hatice Duygu Saatcioglu

    Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2210-0005
  2. Motohiro Kano

    Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Heiko Horn

    Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4898-0557
  4. Lihua Zhang

    Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Wesley Samore

    Department of Pathology, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Nicholas Nagykery

    Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Marie-Charlotte Meinsohn

    Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Minsuk Hyun

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Rana Suliman

    Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Joy Poulo

    Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Jennifer Hsu

    Department of Gynecology and Reproductive Biology, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Caitlin Sacha

    Department of Gynecology and Reproductive Biology, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Dan Wang

    Horae Gene Therapy Center, University of Massachusetts, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Guangping Gao

    Horae Gene Therapy Center, University of Massachusetts, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Kasper Lage

    Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Esther Oliva

    Department of Pathology, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Mary E Morris Sabatini

    Department of Gynecology and Reproductive Biology, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Patricia K Donahoe

    Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. David Pépin

    Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States
    For correspondence
    dpepin@mgh.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2046-6708

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).

Reviewing Editor

  1. Hao Zhu, University of Texas Southwestern Medical Center, United States

Version history

  1. Received: February 25, 2019
  2. Accepted: June 24, 2019
  3. Accepted Manuscript published: June 24, 2019 (version 1)
  4. Version of Record published: July 23, 2019 (version 2)

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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  1. Hatice Duygu Saatcioglu
  2. Motohiro Kano
  3. Heiko Horn
  4. Lihua Zhang
  5. Wesley Samore
  6. Nicholas Nagykery
  7. Marie-Charlotte Meinsohn
  8. Minsuk Hyun
  9. Rana Suliman
  10. Joy Poulo
  11. Jennifer Hsu
  12. Caitlin Sacha
  13. Dan Wang
  14. Guangping Gao
  15. Kasper Lage
  16. Esther Oliva
  17. Mary E Morris Sabatini
  18. Patricia K Donahoe
  19. David Pépin
(2019)
Single-cell sequencing of neonatal uterus reveals an endometrial progenitor indispensable for fertility
eLife 8:e46349.
https://doi.org/10.7554/eLife.46349

Share this article

https://doi.org/10.7554/eLife.46349

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