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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Frontiers Media S.A.
2022-02-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2022.792719/full |
| _version_ | 1818872178680004608 |
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| author | Bi Liu Bi Liu Xia Wang Xia Wang Linan Jiang Jianhua Xu Yitshak Zohar Guang Yao |
| author_facet | Bi Liu Bi Liu Xia Wang Xia Wang Linan Jiang Jianhua Xu Yitshak Zohar Guang Yao |
| author_sort | Bi Liu |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-19T12:34:41Z |
| format | Article |
| id | doaj.art-df07caa816c5433c9b5f6fe9ec4c3cbc |
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| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-19T12:34:41Z |
| publishDate | 2022-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-df07caa816c5433c9b5f6fe9ec4c3cbc2022-12-21T20:21:12ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2022-02-011010.3389/fcell.2022.792719792719Extracellular Fluid Flow Induces Shallow Quiescence Through Physical and Biochemical CuesBi Liu0Bi Liu1Xia Wang2Xia Wang3Linan Jiang4Jianhua Xu5Yitshak Zohar6Guang Yao7School of Pharmacy, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou, ChinaDepartment of Molecular and Cellular Biology, University of Arizona, Tucson, AZ, United StatesDepartment of Molecular and Cellular Biology, University of Arizona, Tucson, AZ, United StatesCollege of Animal Science and Technology, Northwest A&F University, Yangling, ChinaAerospace and Mechanical Engineering, University of Arizona, Tucson, AZ, United StatesSchool of Pharmacy, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou, ChinaAerospace and Mechanical Engineering, University of Arizona, Tucson, AZ, United StatesDepartment of Molecular and Cellular Biology, University of Arizona, Tucson, AZ, United StatesThe 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.https://www.frontiersin.org/articles/10.3389/fcell.2022.792719/fullcellular quiescencequiescence depthextracellular fluid flowflow shear stressextracellular factorsmicroenvironment |
| spellingShingle | Bi Liu Bi Liu Xia Wang Xia Wang Linan Jiang Jianhua Xu Yitshak Zohar Guang Yao Extracellular Fluid Flow Induces Shallow Quiescence Through Physical and Biochemical Cues Frontiers in Cell and Developmental Biology cellular quiescence quiescence depth extracellular fluid flow flow shear stress extracellular factors microenvironment |
| 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 | cellular quiescence quiescence depth extracellular fluid flow flow shear stress extracellular factors microenvironment |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2022.792719/full |
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