Abstract
Cell competition is a social cellular phenomenon in which unfit cells are selectively eliminated to maintain tissue homeostasis.1-3 Recent studies have revealed that mechanical forces induce competitive cell-cell interactions in Drosophila.4-6 This mechanical cell competition has also been reported to play an important role in mammalian cells, using Madin-Darby canine kidney (MDCK) cells depleted of a polarity regulator Scribble in a tetracycline-inducible manner (scribKD cells).7scribKD cells are hypersensitive to crowding due to the lower homeostatic density than wild-type (WT) cells,7,8 and in the context of cell competition, scribKD cells are compacted and eliminated by WT cells.7-10 Although p38 and p53 are involved in this process,7,10 the molecular mechanism by which WT cells recognize and mechanically eliminate scribKD cells remains unclear. Here, we report that scribKD cells secrete fibroblast growth factor 21 (FGF21) to drive cell competition. Knockdown of FGF21 in scribKD cells or loss of FGFR1 in WT cells suppresses cell competition, suggesting that WT cells recognize scribKD cells through FGF21. FGF21-containing culture medium of scribKD cells activates cell motility. Moreover, FGF21 promotes the compression and elimination of scribKD cells by attracting surrounding WT cells. We also demonstrate that activation of the apoptosis signal-regulating kinase 1 (ASK1)-p38 pathway in scribKD cells induces FGF21 to drive cell competition. Our findings reveal a mechanism whereby WT cells mechanically eliminate scribKD cells and propose a new function for FGF21 in cell-cell communication.
Highlights
S) derived from scribKD cells might activate the motility of WT cells, which may promote the compression of scribKD colonies
We observed that the density of scribKD cells was remarkably increased after tetracycline addition compared to that of WT cells in cell competition, suggesting that scribKD cells were compacted (Figure S1B).[7,8,9]
We speculated that certain soluble factor(s) derived from scribKD cells might activate the motility of WT cells, which may promote the compression of scribKD colonies
Summary
S) derived from scribKD cells might activate the motility of WT cells, which may promote the compression of scribKD colonies. To precisely observe the movement of WT cells, we established a WT cell line stably expressing a red fluorescent reporter in the cell nucleus and treated the cells with conditioned medium derived from scribKD cell cultures. After treating with conditioned medium of scribKD cells cultured with Tet, WT cells acquired enhanced motility and showed a flattened morphology, while cell-cell contacts were mostly maintained (Figure 1B; small interfering RNA [siRNA] [À] Tet [+] in Video S2). The addition of conditioned medium of scribKD cells cultured without Tet did not affect the movement of WT cells (Figure 1B; siRNA [À] Tet [À] in Video S2). These data suggest that scribKD cellderived soluble factor(s) may activate the movement of
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