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'
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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Microglia exhibit both maladaptive and adaptive roles in the pathogenesis of neurodegenerative diseases and have emerged as a cellular target for central nervous system (CNS) disorders, including those affecting the retina. Replacing maladaptive microglia, such as those impacted by aging or over-activation, with exogenous microglia that can enable adaptive functions has been proposed as a potential therapeutic strategy for neurodegenerative diseases. To investigate microglia replacement as an approach for retinal diseases, we first employed a protocol to efficiently generate human-induced pluripotent stem cell (hiPSC)-derived microglia in quantities sufficient for in vivo transplantation. These cells demonstrated expression of microglia-enriched genes and showed typical microglial functions such as LPS-induced responses and phagocytosis. We then performed xenotransplantation of these hiPSC-derived microglia into the subretinal space of adult mice whose endogenous retinal microglia have been pharmacologically depleted. Long-term analysis post-transplantation demonstrated that transplanted hiPSC-derived microglia successfully integrated into the neuroretina as ramified cells, occupying positions previously filled by the endogenous microglia and expressed microglia homeostatic markers such as P2ry12 and Tmem119. Furthermore, these cells were found juxtaposed alongside residual endogenous murine microglia for up to 8 months in the retina, indicating their ability to establish a stable homeostatic state in vivo. Following retinal pigment epithelial cell injury, transplanted microglia demonstrated responses typical of endogenous microglia, including migration, proliferation, and phagocytosis. Our findings indicate the feasibility of microglial transplantation and integration in the retina and suggest that modulating microglia through replacement may be a therapeutic strategy for treating neurodegenerative retinal diseases.
