Interleukin-6 is an activator of pituitary stem cells upon local damage, a competence quenched in the aging gland

Annelies Vennekens, Emma Laporte, Florian Hermans, Benoit Cox, Elodie Modave, Adrian Janiszewski, Charlotte Nys, Hiroto Kobayashi, Bert Malengier-Devlies, Joel Chappell, Patrick Matthys, Marie-Isabelle Garcia, Vincent Pasque, Diether Lambrechts, Hugo Vankelecom

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number25
DOIs
Publication statusPublished - 22 Jun 2021

Keywords / Materials (for Non-textual outputs)

  • Aging/pathology
  • Animals
  • Cell Proliferation
  • Inflammation/pathology
  • Interleukin-6/metabolism
  • Mice
  • Organoids/pathology
  • Phenotype
  • Pituitary Gland/pathology
  • Single-Cell Analysis
  • Stem Cells/pathology
  • Transcriptome/genetics
  • Up-Regulation/genetics

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