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
{"title":"膜电位介导多细胞稳态的一种古老的机械转导机制。","authors":"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","doi":"10.1101/2023.11.02.565386","DOIUrl":null,"url":null,"abstract":"<p><p>Membrane potential is a property of all living cells<sup>1</sup>. Nevertheless, its physiological role in non-excitable cells is poorly understood. Resting membrane potential is typically considered fixed and under tight homeostatic control<sup>2</sup>. 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 Hippo<sup>3-9</sup>, 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 <i>Xenopus</i> 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.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10635089/pdf/","citationCount":"0","resultStr":"{\"title\":\"Membrane potential as master regulator of cellular mechano-transduction.\",\"authors\":\"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\",\"doi\":\"10.1101/2023.11.02.565386\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Membrane potential is a property of all living cells<sup>1</sup>. Nevertheless, its physiological role in non-excitable cells is poorly understood. Resting membrane potential is typically considered fixed and under tight homeostatic control<sup>2</sup>. 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 Hippo<sup>3-9</sup>, 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 <i>Xenopus</i> 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.</p>\",\"PeriodicalId\":72407,\"journal\":{\"name\":\"bioRxiv : the preprint server for biology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-07-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10635089/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"bioRxiv : the preprint server for biology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1101/2023.11.02.565386\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"bioRxiv : the preprint server for biology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2023.11.02.565386","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
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.