Pituitary stem cells produce paracrine WNT signals to control the expansion of their descendant progenitor cells
- King's College London, United Kingdom
- Agency for Science, Technology and Research, Singapore
- Institut de Génomique Fonctionnelle, France
- Howard Hughes Medical Institute, Stanford University School of Medicine, United States
- Stanford University, United States
- University College London, United Kingdom
- Université Côte d'Azur, France
- 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
Article and author information
Author details
Cynthia Lilian Andoniadou
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
- Marianne E Bronner, California Institute of Technology, United States
Version history
- Received: May 20, 2020
- Accepted: January 4, 2021
- Accepted Manuscript published: January 5, 2021 (version 1)
- 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.
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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
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- Developmental Biology
- Stem Cells and Regenerative Medicine
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.
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- Developmental Biology
- Stem Cells and Regenerative Medicine
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.
