膜电位介导多细胞稳态的一种古老的机械转导机制。

Avik Mukherjee, Yanqing Huang, Jens Elgeti, Seungeun Oh, Jose G Abreu, Anjali Rebecca Neliat, Janik Schüttler, Dan-Dan Su, Christophe Dupre, Nina Catherine Benites, Xili Liu, Leonid Peshkin, Mihail Barboiu, Hugo Stocker, Marc W Kirschner, Markus Basan
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引用次数: 0

摘要

膜电位是所有活细胞的特性。然而,其在不可兴奋细胞中的生理作用尚不清楚。静息膜电位通常被认为对特定的细胞类型是固定的,并受到严格的稳态控制,类似于哺乳动物的体温。与这种被广泛接受的范式相反,我们发现膜电位是一种动态特性,直接反映了组织密度和作用在细胞上的机械力。作为准瞬时的、全局的密度和机械压力读数,膜电位通过影响膜中蛋白质的构象和聚类3,4以及关键信号离子的跨膜通量5,6,与信号转导网络相结合。事实上,我们发现重要的机械传感通路YAP, Jnk和p38 7-121314直接受膜电位控制。我们进一步表明,通过膜电位的机械转导在上皮组织的稳态中起着关键作用,通过控制细胞的增殖和细胞挤压来设定组织密度。此外,机械拉伸引发的去极化波提高了伤口愈合的速度。通过膜电位的机械转导可能构成了多细胞生物中一种古老的稳态机制,可能是可兴奋组织和神经元机械传感进化的垫脚石。膜电位介导的稳态调节的破坏可能有助于肿瘤的生长。
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Membrane potential as master regulator of cellular mechano-transduction.

Membrane potential is a property of all living cells1. Nevertheless, its physiological role in non-excitable cells is poorly understood. Resting membrane potential is typically considered fixed and under tight homeostatic control2. Contrary to this paradigm, we find that membrane potential is a dynamic property that directly reflects mechanical forces acting on the cell and that cells use membrane potential to assess their biomechanical state. We show that several important mechano-sensitive signal transduction pathways, like MAPK and Hippo3-9, are directly controlled by membrane potential and this signaling is mediated by upstream membrane-bound receptors, including FAT1. We further show that mechano-transduction via membrane potential plays a critical role in the homeostasis of epithelial tissues, setting cellular biomass density and cell number density by controlling proliferation and cell elimination. In epithelial scratch wound assays, as well as Xenopus tadpole tail regeneration, we observe a wave of depolarization caused by a drop in cellular biomass density due to mechanical stretch and we show that this depolarization wave is critical for wound closure. Together, these data are explained by a first-principles biophysical model, which demonstrates that membrane potential is physically coupled to mechanical pressure and cellular biomass density. Membrane potential thereby provides a quasi-instantaneous, global readout of the biophysical state of the cell and in turn regulates cell growth, resulting in homeostatic feedback control of biomass density and cell number density in tissues. This interplay may be an ancient mechanism for growth control in multi-cellular organisms and its misregulation may play an important role in tumorigenesis.

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