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

• Published in: Cellular and molecular life sciences : CMLS Vol. 79; no. 2; p. 82
• Main Authors: Lehmann, Johannes, Narcisi, Roberto, Franceschini, Natasja, Chatzivasileiou, Danai, Boer, Cindy G., Koevoet, Wendy J. L. M., Putavet, Diana, Drabek, Dubravka, van Haperen, Rien, de Keizer, Peter L. J., van Osch, Gerjo J. V. M., ten Berge, Derk
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.02.2022; Springer Nature B.V
• Subjects: Aging; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell cycle; Cell Proliferation; Cells, Cultured; Cytokines; Degenerative diseases; Humans; Interleukin 6; Life Sciences; Mesenchymal stem cells; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; Middle Aged; Mode of action; NF-κB protein; Original; Original Article; Paracrine signalling; Phenotypes; Secretome; Senescence; Senescence-Associated Secretory Phenotype; Signaling; Stem cells; Wnt protein; Wnt Signaling Pathway; Wnt3A Protein - metabolism; β-Catenin; Secondary senescence; Paracrine senescence; Multipotent stromal cells; Cell cycle
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-021-04035-x

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.