Cell competition is a social cellular phenomenon in which unfit cells are selectively eliminated to maintain tissue homeostasis.1, 2, 3 Recent studies have revealed that mechanical forces induce competitive cell-cell interactions in Drosophila.4, 5, 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 (scrib^KD cells).⁷ scrib^KD 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, scrib^KD cells are compacted and eliminated by WT cells.7, 8, 9, 10 Although p38 and p53 are involved in this process,^7,10 the molecular mechanism by which WT cells recognize and mechanically eliminate scrib^KD cells remains unclear. Here, we report that scrib^KD cells secrete fibroblast growth factor 21 (FGF21) to drive cell competition. Knockdown of FGF21 in scrib^KD cells or loss of FGFR1 in WT cells suppresses cell competition, suggesting that WT cells recognize scrib^KD cells through FGF21. FGF21-containing culture medium of scrib^KD cells activates cell motility. Moreover, FGF21 promotes the compression and elimination of scrib^KD cells by attracting surrounding WT cells. We also demonstrate that activation of the apoptosis signal-regulating kinase 1 (ASK1)-p38 pathway in scrib^KD cells induces FGF21 to drive cell competition. Our findings reveal a mechanism whereby WT cells mechanically eliminate scrib^KD cells and propose a new function for FGF21 in cell-cell communication.

细胞竞争是一种社会细胞现象，其中不适合的细胞被选择性消除以维持组织稳态。1, 2, 3 最近的研究表明，机械力会在果蝇中诱导竞争性细胞 - 细胞相互作用.4, 5, 6 这种机械细胞竞争具有也被报道在哺乳动物细胞中发挥重要作用，使用以四环素诱导方式耗尽极性调节剂 Scribble 的 Madin-Darby 犬肾 (MDCK) 细胞 ( scrib ^KD细胞)。⁷ scrib ^KD细胞由于比野生型 (WT) 细胞^{7 、8}更低的稳态密度而对拥挤敏感，并且在细胞竞争的情况下，scrib ^KD细胞被 WT 细胞压实和消除。7, 8, 9, 10 尽管 p38 和 p53 参与了这一过程，^{7 , 10 WT 细胞识别和机械消除}划线^KD细胞的分子机制仍不清楚。在这里，我们报告了scrib ^KD细胞分泌成纤维细胞生长因子 21 (FGF21) 来驱动细胞竞争。scrib ^KD细胞中 FGF21 的敲低或 WT 细胞中 FGFR1 的缺失抑制了细胞竞争，表明 WT细胞通过 FGF21识别scrib ^KD细胞。scrib ^KD的含FGF21培养基细胞激活细胞运动。此外，FGF21通过吸引周围的 WT 细胞来促进scrib ^KD细胞的压缩和消除。我们还证明了scrib ^KD细胞中凋亡信号调节激酶 1 (ASK1)-p38 通路的激活诱导 FGF21 驱动细胞竞争。我们的研究结果揭示了一种机制，即 WT 细胞机械地消除^{了 KD}细胞，并提出了 FGF21 在细胞间通讯中的新功能。