Interleukin-6 is an activator of pituitary stem cells upon local damage, a competence quenched in the aging gland
- 14 June 2021
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 118 (25)
- https://doi.org/10.1073/pnas.2100052118
Abstract
Stem cells in the adult pituitary are quiescent yet show acute activation upon tissue injury. The molecular mechanisms underlying this reaction are completely unknown. We applied single-cell transcriptomics to start unraveling the acute pituitary stem cell activation process as occurring upon targeted endocrine cell–ablation damage. This stem cell reaction was contrasted with the aging (middle-aged) pituitary, known to have lost damage-repair capacity. Stem cells in the aging pituitary show regressed proliferative activation upon injury and diminished in vitro organoid formation. Single-cell RNA sequencing uncovered interleukin-6 (IL-6) as being up-regulated upon damage, however only in young but not aging pituitary. Administering IL-6 to young mice promptly triggered pituitary stem cell proliferation, while blocking IL-6 or associated signaling pathways inhibited such reaction to damage. By contrast, IL-6 did not generate a pituitary stem cell activation response in aging mice, coinciding with elevated basal IL-6 levels and raised inflammatory state in the aging gland (inflammaging). Intriguingly, in vitro stem cell activation by IL-6 was discerned in organoid culture not only from young but also from aging pituitary, indicating that the aging gland’s stem cells retain intrinsic activatability in vivo, likely impeded by the prevailing inflammatory tissue milieu. Importantly, IL-6 supplementation strongly enhanced the growth capability of pituitary stem cell organoids, thereby expanding their potential as an experimental model. Our study identifies IL-6 as a pituitary stem cell activator upon local damage, a competence quenched at aging, concomitant with raised IL-6/inflammatory levels in the older gland. These insights may open the way to interfering with pituitary aging.Keywords
Funding Information
- Fonds Wetenschappelijk Onderzoek (1141717N)
- Fonds Wetenschappelijk Onderzoek (11A3320N)
- Fonds Wetenschappelijk Onderzoek (11W9215N)
- Fonds Wetenschappelijk Onderzoek (1158318N)
- Fonds Wetenschappelijk Onderzoek (1S14218N)
This publication has 55 references indexed in Scilit:
- Mobilized Adult Pituitary Stem Cells Contribute to Endocrine Regeneration in Response to Physiological DemandCell Stem Cell, 2013
- Interleukin‐6 myokine signaling in skeletal muscle: a double‐edged sword?The FEBS Journal, 2013
- Age-associated inflammation inhibits epidermal stem cell functionGenes & Development, 2012
- Tissue-Specific Stem Cells: Lessons from the Skeletal Muscle Satellite CellCell Stem Cell, 2012
- Activated Phenotype of the Pituitary Stem/Progenitor Cell Compartment During the Early-Postnatal Maturation Phase of the GlandStem Cells and Development, 2012
- Repeated TLR9 stimulation results in macrophage activation syndrome–like disease in miceJCI Insight, 2011
- Pituitary Progenitor Cells Tracked Down by Side Population DissectionThe International Journal of Cell Cloning, 2009
- Trop2 identifies a subpopulation of murine and human prostate basal cells with stem cell characteristicsProceedings of the National Academy of Sciences of the United States of America, 2008
- SOX2-expressing progenitor cells generate all of the major cell types in the adult mouse pituitary glandProceedings of the National Academy of Sciences of the United States of America, 2008
- Interleukin-6 Is an Essential Regulator of Satellite Cell-Mediated Skeletal Muscle HypertrophyCell Metabolism, 2008