Pituitary stem cells produce paracrine WNT signals to control the expansion of their descendant progenitor cells

  1. John P Russell
  2. Xinhong Lim
  3. Alice Santambrogio
  4. Val Yianni
  5. Yasmine Kemkem
  6. Bruce Wang
  7. Matthew Fish
  8. Scott Haston
  9. Anaëlle Grabek
  10. Shirleen Hallang
  11. Emily J Lodge
  12. Amanda L Patist
  13. Andreas Schedl
  14. Patrice Mollard
  15. Roel Nusse
  16. Cynthia Lilian Andoniadou  Is a corresponding author
  1. King's College London, United Kingdom
  2. Agency for Science, Technology and Research, Singapore
  3. Institut de Génomique Fonctionnelle, France
  4. Howard Hughes Medical Institute, Stanford University School of Medicine, United States
  5. Stanford University, United States
  6. University College London, United Kingdom
  7. Université Côte d'Azur, France
  8. University of Manchester, United Kingdom

Abstract

In response to physiological demand, the pituitary gland generates new hormone-secreting cells from committed progenitor cells throughout life. It remains unclear to what extent pituitary stem cells (PSCs), which uniquely express SOX2, contribute to pituitary growth and renewal. Moreover, neither the signals that drive proliferation nor their sources have been elucidated. We have used genetic approaches in the mouse, showing that the WNT pathway is essential for proliferation of all lineages in the gland. We reveal that SOX2+ stem cells are a key source of WNT ligands. By blocking secretion of WNTs from SOX2+ PSCs in vivo, we demonstrate that proliferation of neighbouring committed progenitor cells declines, demonstrating that progenitor multiplication depends on the paracrine WNT secretion from SOX2+ PSCs. Our results indicate that stem cells can hold additional roles in tissue expansion and homeostasis, acting as paracrine signalling centres to coordinate the proliferation of neighbouring cells.

Data availability

Sequencing data can be accessed through the following link: https://www.ncbi.nlm.nih.gov/bioproject/PRJNA421806

The following data sets were generated

Article and author information

Author details

  1. John P Russell

    Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  2. Xinhong Lim

    Skin Research Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4725-5161
  3. Alice Santambrogio

    Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  4. Val Yianni

    Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9857-7577
  5. Yasmine Kemkem

    Physiology, Institut de Génomique Fonctionnelle, Montpellier, France
    Competing interests
    No competing interests declared.
  6. Bruce Wang

    Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, United States
    Competing interests
    No competing interests declared.
  7. Matthew Fish

    Developmental Biology, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
  8. Scott Haston

    Institute of Child Health, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3928-4808
  9. Anaëlle Grabek

    Inserm, CNSR, iBV, Université Côte d'Azur, Nice, France
    Competing interests
    No competing interests declared.
  10. Shirleen Hallang

    Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  11. Emily J Lodge

    Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0932-8515
  12. Amanda L Patist

    Centre for Endocrinology and Diabetes, University of Manchester, Manchester, United Kingdom
    Competing interests
    No competing interests declared.
  13. Andreas Schedl

    Inserm, CNSR, iBV, Université Côte d'Azur, Nice, France
    Competing interests
    No competing interests declared.
  14. Patrice Mollard

    Physiology, Institut de Génomique Fonctionnelle, Montpellier, France
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2324-7589
  15. Roel Nusse

    Developmental Biology, Stanford University, Stanford, United States
    Competing interests
    Roel Nusse, Reviewing editor, eLife.
  16. Cynthia Lilian Andoniadou

    Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom
    For correspondence
    cynthia.andoniadou@kcl.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4311-5855

Funding

Medical Research Council (MR/L016729/1)

  • Cynthia Lilian Andoniadou

Medical Research Council (MR/T012153/1)

  • Cynthia Lilian Andoniadou

Deutsche Forschungsgemeinschaft (314061271 - TRR 205)

  • Cynthia Lilian Andoniadou

Howard Hughes Medical Institute

  • Roel Nusse

Agence Nationale de la Recherche (ANR-18-CE14-0017)

  • Patrice Mollard

Fondation pour la Recherche Médicale (DEQ20150331732)

  • Patrice Mollard

Lister Institute of Preventive Medicine

  • Cynthia Lilian Andoniadou

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 under compliance of the Animals (Scientific Procedures) Act 1986, Home Office License (P5F0A1579) and KCL Biological Safety approval for project 'Function and Regulation of Pituitary Stem Cells in Mammals'

Reviewing Editor

  1. Marianne E Bronner, California Institute of Technology, United States

Version history

  1. Received: May 20, 2020
  2. Accepted: January 4, 2021
  3. Accepted Manuscript published: January 5, 2021 (version 1)
  4. Version of Record published: January 12, 2021 (version 2)

Copyright

© 2021, Russell 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.

Metrics

  • 2,155
    Page views
  • 305
    Downloads
  • 16
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. John P Russell
  2. Xinhong Lim
  3. Alice Santambrogio
  4. Val Yianni
  5. Yasmine Kemkem
  6. Bruce Wang
  7. Matthew Fish
  8. Scott Haston
  9. Anaëlle Grabek
  10. Shirleen Hallang
  11. Emily J Lodge
  12. Amanda L Patist
  13. Andreas Schedl
  14. Patrice Mollard
  15. Roel Nusse
  16. Cynthia Lilian Andoniadou
(2021)
Pituitary stem cells produce paracrine WNT signals to control the expansion of their descendant progenitor cells
eLife 10:e59142.
https://doi.org/10.7554/eLife.59142

Further reading

    1. Developmental Biology
    2. Stem Cells and Regenerative Medicine
    Valeria Scagliotti, Maria Lillina Vignola ... Marika Charalambous
    Research Article Updated

    Co-regulated genes of the Imprinted Gene Network are involved in the control of growth and body size, and imprinted gene dysfunction underlies human paediatric disorders involving the endocrine system. Imprinted genes are highly expressed in the pituitary gland, among them, Dlk1, a paternally expressed gene whose membrane-bound and secreted protein products can regulate proliferation and differentiation of multiple stem cell populations. Dosage of circulating DLK1 has been previously implicated in the control of growth through unknown molecular mechanisms. Here we generate a series of mouse genetic models to modify levels of Dlk1 expression in the pituitary gland and demonstrate that the dosage of DLK1 modulates the process of stem cell commitment with lifelong impact on pituitary gland size. We establish that stem cells are a critical source of DLK1, where embryonic disruption alters proliferation in the anterior pituitary, leading to long-lasting consequences on growth hormone secretion later in life.

    1. Developmental Biology
    2. Stem Cells and Regenerative Medicine
    Damien Detraux, Marino Caruso ... Patricia Renard
    Research Article Updated

    Using embryonic stem cells (ESCs) in regenerative medicine or in disease modeling requires a complete understanding of these cells. Two main distinct developmental states of ESCs have been stabilized in vitro, a naïve pre-implantation stage and a primed post-implantation stage. Based on two recently published CRISPR-Cas9 knockout functional screens, we show here that the exit of the naïve state is impaired upon heme biosynthesis pathway blockade, linked in mESCs to the incapacity to activate MAPK- and TGFβ-dependent signaling pathways after succinate accumulation. In addition, heme synthesis inhibition promotes the acquisition of 2 cell-like cells in a heme-independent manner caused by a mitochondrial succinate accumulation and leakage out of the cell. We further demonstrate that extracellular succinate acts as a paracrine/autocrine signal, able to trigger the 2C-like reprogramming through the activation of its plasma membrane receptor, SUCNR1. Overall, this study unveils a new mechanism underlying the maintenance of pluripotency under the control of heme synthesis.