A feedback loop between lamellipodial extension and HGF-ERK signaling specifies leader cells during collective cell migration
A feedback loop between lamellipodial extension and HGF-ERK signaling specifies leader cells during collective cell migration
复制标题
DOI：
10.1016/j.devcel.2022.09.003
复制
发表时间：
2022-10-10
影响因子：
11.8
通讯作者：
Matsuda, Michiyuki
中科院分区：
文献类型：
--
作者：
Hino, Naoya;Matsuda, Kimiya;Matsuda, Michiyuki
在开始集体细胞迁移，在自由边缘的细胞被指定为领导细胞，然而，领导细胞规范的机制仍然难以捉摸。在这里，我们表明，从机械限制释放后，板状体的延伸导致持续的细胞外信号调节激酶（ERK）激活和领导细胞规范的基础。通过使用基于Forster共振能量转移（FRET）的生物传感器对Madin-Darby犬肾（MDCK）细胞和小鼠表皮进行的实时成像显示，前导细胞以肝细胞生长因子（HGF）依赖的方式表现出持续的ERK激活。同时，跟随细胞表现出振荡的ERK激活波在表皮生长因子（EGF）信号依赖的方式。游离边缘的片状伪足延伸增加了细胞对HGF的敏感性。HGF依赖的ERK激活，反过来，促进片状伪足延伸，从而形成细胞延伸和ERK激活之间的正反馈回路，并指定在自由边缘的细胞作为领导细胞。我们的研究结果表明，整合的物理和生化线索的领导细胞规范在集体细胞迁移的基础。
Upon the initiation of collective cell migration, the cells at the free edge are specified as leader cells; however, the mechanism underlying the leader cell specification remains elusive. Here, we show that lamellipodial extension after the release from mechanical confinement causes sustained extracellular signal-regulated kinase (ERK) activation and underlies the leader cell specification. Live-imaging of Madin-Darby canine kidney (MDCK) cells and mouse epidermis through the use of Forster resonance energy transfer (FRET)-based bio sensors showed that leader cells exhibit sustained ERK activation in a hepatocyte growth factor (HGF)-dependent manner. Meanwhile, follower cells exhibit oscillatory ERK activation waves in an epidermal growth factor (EGF) signaling-dependent manner. Lamellipodial extension at the free edge increases the cellular sensitivity to HGF. The HGF-dependent ERK activation, in turn, promotes lamellipodial extension, thereby forming a positive feedback loop between cell extension and ERK activation and specifying the cells at the free edge as the leader cells. Our findings show that the integration of physical and biochemical cues underlies the leader cell specification during collective cell migration.