WNT signals inhibit paracrine induction of senescence in human multipotent stromal cells

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 senescence in cultured human adult multipotent stromal cells (MSCs) by limiting paracrine senescence. 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-kB 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. // The RNAseq data in particular focusses on the transcriptome changes in MSCs occuring in vitro culture over four passages in presence or absence of growth factors WNT3A and FGF2. RNA sequencing of 18 human bone marrow derived multipotent stromal cell cultures from three bone marrow donors (female, post-menopause age) [6 per donor]; cells were harvested at two different time points (passages): passage 1 after six hours culture with either: FGF2 and WNT3A, FGF2 and CHAPS (vehicle for WNT3A), WNT3A only (FGF2 was dissolved in cell culture medium, thus no vehicle), CHAPS only; passage 4 after culture since passage 1 in either: FGF2 and WNT3A or FGF2 and CHAPS