WNT/beta-catenin signalling interrupts a senescence-induction cascade in human mesenchymal stem cells that restricts their expansion

Johannes Lehmann, Roberto Narcisi, Natasja Franceschini, Danai Chatzivasileiou, Cindy G. Boer, Wendy J.L.M. Koevoet, Diana Putavet, Dubravka Drabek, Rien van Haperen, Peter L.J. de Keizer, Gerjo J.V.M. van Osch, Derk ten Berge*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Senescence, the irreversible cell cycle arrest of damaged cells, is accompanied by a deleterious pro-inflammatory senescence-associated secretory phenotype (SASP). Senescence and the SASP are major factors in aging, cancer, and degenerative diseases, and interfere with the expansion of adult cells in vitro, yet little is known about how to counteract their induction and deleterious effects. Paracrine signals are increasingly recognized as important senescence triggers and understanding their regulation and mode of action may provide novel opportunities to reduce senescence-induced inflammation and improve cell-based therapies. Here, we show that the signalling protein WNT3A counteracts the induction of paracrine senescence in cultured human adult mesenchymal stem cells (MSCs). We find that entry into senescence in a small subpopulation of MSCs triggers a secretome that causes a feed-forward signalling cascade that with increasing speed induces healthy cells into senescence. WNT signals interrupt this cascade by repressing cytokines that mediate this induction of senescence. Inhibition of those mediators by interference with NF-κB or interleukin 6 signalling reduced paracrine senescence in absence of WNT3A and promoted the expansion of MSCs. Our work reveals how WNT signals can antagonize senescence and has relevance not only for expansion of adult cells but can also provide new insights into senescence-associated inflammatory and degenerative diseases.

Original languageEnglish
Article number82
JournalCellular and Molecular Life Sciences
Issue number2
Publication statusPublished - 20 Jan 2022

Bibliographical note

Funding Information:
This research was supported by FFG grant-CartiScaff (Gerjo van Osch), ZonMW grant 116006104 (Derk ten Berge), KWF grant UMCU7141 (Peter de Keizer).

Publisher Copyright:
© 2022, The Author(s).


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