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Extracellular Fluid Flow Induces Shallow Quiescence Through Physical and Biochemical Cues

The balance between cell quiescence and proliferation is fundamental to tissue physiology and homeostasis. Recent studies have shown that quiescence is not a passive and homogeneous state but actively maintained and heterogeneous. These cellular characteristics associated with quiescence were observ...

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Autores principales: Liu, Bi, Wang, Xia, Jiang, Linan, Xu, Jianhua, Zohar, Yitshak, Yao, Guang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8912726/
https://www.ncbi.nlm.nih.gov/pubmed/35281101
http://dx.doi.org/10.3389/fcell.2022.792719
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author Liu, Bi
Wang, Xia
Jiang, Linan
Xu, Jianhua
Zohar, Yitshak
Yao, Guang
author_facet Liu, Bi
Wang, Xia
Jiang, Linan
Xu, Jianhua
Zohar, Yitshak
Yao, Guang
author_sort Liu, Bi
collection PubMed
description The balance between cell quiescence and proliferation is fundamental to tissue physiology and homeostasis. Recent studies have shown that quiescence is not a passive and homogeneous state but actively maintained and heterogeneous. These cellular characteristics associated with quiescence were observed primarily in cultured cells under a static medium. However, cells in vivo face different microenvironmental conditions, particularly, under interstitial fluid flows distributed through extracellular matrices. Interstitial fluid flow exerts shear stress on cells and matrix strain, and results in continuous replacement of extracellular factors. In this study, we analyzed individual cells under varying fluid flow rates in microfluidic devices. We found quiescence characteristics previously identified under conventional static medium, including serum signal-dependant quiescence entry and exit and time-dependant quiescence deepening, are also present under continuous fluid flow. Furthermore, increasing the flow rate drives cells to shallower quiescence and become more likely to reenter the cell cycle upon growth stimulation. This effect is due to flow-induced physical and biochemical cues. Specifically, increasing shear stress or extracellular factor replacement individually, without altering other parameters, results in shallow quiescence. We show our experimental results can be quantitatively explained by a mathematical model connecting extracellular fluid flow to an Rb-E2f bistable switch that regulates the quiescence-to-proliferation transition. Our findings uncover a previously unappreciated mechanism that likely underlies the heterogeneous responses of quiescent cells for tissue repair and regeneration in different physiological tissue microenvironments.
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spelling pubmed-89127262022-03-11 Extracellular Fluid Flow Induces Shallow Quiescence Through Physical and Biochemical Cues Liu, Bi Wang, Xia Jiang, Linan Xu, Jianhua Zohar, Yitshak Yao, Guang Front Cell Dev Biol Cell and Developmental Biology The balance between cell quiescence and proliferation is fundamental to tissue physiology and homeostasis. Recent studies have shown that quiescence is not a passive and homogeneous state but actively maintained and heterogeneous. These cellular characteristics associated with quiescence were observed primarily in cultured cells under a static medium. However, cells in vivo face different microenvironmental conditions, particularly, under interstitial fluid flows distributed through extracellular matrices. Interstitial fluid flow exerts shear stress on cells and matrix strain, and results in continuous replacement of extracellular factors. In this study, we analyzed individual cells under varying fluid flow rates in microfluidic devices. We found quiescence characteristics previously identified under conventional static medium, including serum signal-dependant quiescence entry and exit and time-dependant quiescence deepening, are also present under continuous fluid flow. Furthermore, increasing the flow rate drives cells to shallower quiescence and become more likely to reenter the cell cycle upon growth stimulation. This effect is due to flow-induced physical and biochemical cues. Specifically, increasing shear stress or extracellular factor replacement individually, without altering other parameters, results in shallow quiescence. We show our experimental results can be quantitatively explained by a mathematical model connecting extracellular fluid flow to an Rb-E2f bistable switch that regulates the quiescence-to-proliferation transition. Our findings uncover a previously unappreciated mechanism that likely underlies the heterogeneous responses of quiescent cells for tissue repair and regeneration in different physiological tissue microenvironments. Frontiers Media S.A. 2022-02-24 /pmc/articles/PMC8912726/ /pubmed/35281101 http://dx.doi.org/10.3389/fcell.2022.792719 Text en Copyright © 2022 Liu, Wang, Jiang, Xu, Zohar and Yao. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Liu, Bi
Wang, Xia
Jiang, Linan
Xu, Jianhua
Zohar, Yitshak
Yao, Guang
Extracellular Fluid Flow Induces Shallow Quiescence Through Physical and Biochemical Cues
title Extracellular Fluid Flow Induces Shallow Quiescence Through Physical and Biochemical Cues
title_full Extracellular Fluid Flow Induces Shallow Quiescence Through Physical and Biochemical Cues
title_fullStr Extracellular Fluid Flow Induces Shallow Quiescence Through Physical and Biochemical Cues
title_full_unstemmed Extracellular Fluid Flow Induces Shallow Quiescence Through Physical and Biochemical Cues
title_short Extracellular Fluid Flow Induces Shallow Quiescence Through Physical and Biochemical Cues
title_sort extracellular fluid flow induces shallow quiescence through physical and biochemical cues
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8912726/
https://www.ncbi.nlm.nih.gov/pubmed/35281101
http://dx.doi.org/10.3389/fcell.2022.792719
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