FGF21 Induced by the ASK1-p38 Pathway Promotes Mechanical Cell Competition by Attracting Cells
FGF21 Induced by the ASK1-p38 Pathway Promotes Mechanical Cell Competition by Attracting Cells
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DOI：
10.1016/j.cub.2020.11.052
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发表时间：
2020-12
期刊：
影响因子：
9.2
通讯作者：
M. Ogawa;Yosuke Kawarazaki;Yasuyuki Fujita;I. Naguro;H. Ichijo
中科院分区：
文献类型：
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作者：
M. Ogawa;Yosuke Kawarazaki;Yasuyuki Fujita;I. Naguro;H. Ichijo
细胞竞争是一种社会细胞现象，在这种现象中，不适合的细胞被选择性地消除，以维持组织的稳态。1-3最近的研究表明，在果蝇中，机械力诱导细胞与细胞之间的竞争性相互作用。4-6据报道，这种机械细胞竞争在哺乳动物细胞中也发挥着重要作用，使用的是以四环素诱导的方式去除极性调节剂Scribble的Madin-Darby犬肾(MDCK)细胞。7cribKD细胞由于比野生型(WT)细胞的稳态密度低，对拥挤高度敏感，7，8，在细胞竞争的背景下，ScribKD细胞被WT细胞压缩和消除。7-10Alp38和P53参与这一过程7，10 WT细胞识别和机械消除CRKD细胞的分子机制尚不清楚。在此，我们报道了ScribKD细胞分泌成纤维细胞生长因子21(FGF21)来驱动细胞竞争。WT细胞中FGF21表达下调KD细胞或FGFR1缺失抑制细胞竞争，提示WT细胞通过FGF21识别KD细胞。含FGF21的KD细胞培养液可激活细胞运动。此外，FGF21通过吸引周围的WT细胞来促进ScribKD细胞的压缩和消除。我们还证明了KD细胞内的凋亡信号调节激酶1(ASK1)-p38通路的激活诱导FGF21驱动细胞竞争。我们的发现揭示了WT细胞机械地清除KD细胞的机制，并提出了FGF21在细胞间通讯中的新功能。
Cell competition is a social cellular phenomenon in which unfit cells are selectively eliminated to maintain tissue homeostasis.1–3Recent studies have revealed that mechanical forces induce competitive cell-cell interactions inDrosophila.4–6This 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 (scribKDcells).7scribKDcells are hypersensitive to crowding due to the lower homeostatic density than wild-type (WT) cells,7,8and in the context of cell competition,scribKDcells are compacted and eliminated by WT cells.7–10Although p38 and p53 are involved in this process,7,10the molecular mechanism by which WT cells recognize and mechanically eliminatescribKDcells remains unclear. Here, we report thatscribKDcells secrete fibroblast growth factor 21 (FGF21) to drive cell competition. Knockdown of FGF21 inscribKDcells or loss of FGFR1 in WT cells suppresses cell competition, suggesting that WT cells recognizescribKDcells through FGF21. FGF21-containing culture medium ofscribKDcells activates cell motility. Moreover, FGF21 promotes the compression and elimination ofscribKDcells by attracting surrounding WT cells. We also demonstrate that activation of the apoptosis signal-regulating kinase 1 (ASK1)-p38 pathway inscribKDcells induces FGF21 to drive cell competition. Our findings reveal a mechanism whereby WT cells mechanically eliminatescribKDcells and propose a new function for FGF21 in cell-cell communication.