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

Johannes Lehmann,Dubravka Drabek,Cindy G Boer,Danai Chatzivasileiou,Natasja Franceschini,Diana Putavet,Peter L J De Keizer,Roberto Narcisi,Derk Ten Berge,Gerjo J V M Van Osch,Wendy J L M Koevoet,Rien Van Haperen

doi:10.1007/s00018-021-04035-x

Abstract

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.

Highlights

Following irreparable damage, healthy cells can enter a state of stable cell cycle arrest termed senescence [1]
The proliferation of human bone marrow-derived mesenchymal stem cells (MSCs) rapidly declines over time, and this can be counteracted by supplementation with WNT3A (Fig. 1a, Supplementary Fig. 1a) confirming our previous findings [32]
To understand how WNT signalling prevented the decline of MSC proliferation, we performed whole transcriptome analysis of early passage (P1) MSCs and of MSCs maintained until passage four (P4) with WNT3A or vehicle control (Fig. 1b)

Summary

Introduction

Healthy cells can enter a state of stable cell cycle arrest termed senescence [1]. Senescence regulates tissue growth during development and can repress. Evidence accumulated that senescent cells affect their environment via their secretome, often termed the senescenceassociated secretory phenotype (SASP) (reviewed in [9]), consisting mostly of pro-inflammatory cytokines, proteases and insulin-growth factor-binding proteins [10, 11]. A subset of SASP factors induces proliferation during wound healing and development [3, 4, 12,13,14]. In other circumstances, SASP factors mediate the spread of senescence to surrounding cells [15,16,17,18,19,20,21]

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Results

Conclusion