![]() Interstitial flow also generates mechanical shear stress on cells, which affects cell morphology, migration, growth, and differentiation ( Jain, 1987 Ng and Swartz, 2003 Tarbell et al., 2005 Swartz and Fleury, 2007 Polacheck et al., 2011 Shirure et al., 2017 Chen et al., 2019). A particular microenvironmental factor is the interstitial fluid flowing over tissue cells, which transports nutrients and other dissolved molecules that influence cellular activities ( Jain, 1987 Swartz and Fleury, 2007 Freund et al., 2012 Yao et al., 2013). The dysregulation of cellular quiescence depth can lead to disrupted tissue homeostasis, exhibiting either an insufficient number of growing cells due to an abnormally deep quiescence, or a depleted pool of quiescent stem and progenitor cells due to an abnormally shallow quiescence ( Orford and Scadden, 2008 Cheung and Rando, 2013 Fujimaki and Yao, 2020).Īlthough dormant and non-proliferative, quiescent cells reside in and interact with dynamic microenvironments. Certain muscle and neural stem cells after tissue injury are examples of shallow quiescent cells, primed to reenter the cell cycle faster upon the next damage ( Rodgers et al., 2014 Llorens-Bobadilla et al., 2015). Hepatocytes in older rats are an example of deeper quiescent cells, displaying a longer delay before reentering the cell cycle and reinitiating DNA replication following partial hepatectomy, as compared to those in younger rats ( Bucher, 1963). Cells in deeper quiescence require stronger growth stimulation and take longer to exit quiescence and reenter the cell cycle than in shallower quiescence ( Augenlicht and Baserga, 1974 Kwon et al., 2017 Fujimaki et al., 2019). The heterogeneity of quiescent cells in their proliferation potential can be described as a graded depth. Recent studies, however, have revealed that quiescence is rather actively maintained and highly heterogeneous ( Coller et al., 2006 Sang et al., 2008 Cheung and Rando, 2013 Spencer et al., 2013 Wang et al., 2017). ![]() Quiescence has long been viewed as a passive cellular state lacking cell cycle activity. Activating quiescent cells (e.g., adult stem and progenitor cells) to proliferate is fundamental to tissue homeostasis and repair ( Coller et al., 2006 Wilson et al., 2008 Li and Clevers, 2010 Cheung and Rando, 2013). Quiescent cells, however, still maintain the potential to proliferate upon physiological signals, making them distinct from other dormant cells that are irreversibly arrested, such as those in senescence or terminal differentiation. Quiescence is a dormant, non-proliferative cellular state. 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. 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. Specifically, increasing shear stress or extracellular factor replacement individually, without altering other parameters, results in shallow quiescence. This effect is due to flow-induced physical and biochemical cues. Furthermore, increasing the flow rate drives cells to shallower quiescence and become more likely to reenter the cell cycle upon growth stimulation. 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. In this study, we analyzed individual cells under varying fluid flow rates in microfluidic devices. Interstitial fluid flow exerts shear stress on cells and matrix strain, and results in continuous replacement of extracellular factors. However, cells in vivo face different microenvironmental conditions, particularly, under interstitial fluid flows distributed through extracellular matrices. These cellular characteristics associated with quiescence were observed primarily in cultured cells under a static medium. Recent studies have shown that quiescence is not a passive and homogeneous state but actively maintained and heterogeneous. The balance between cell quiescence and proliferation is fundamental to tissue physiology and homeostasis. ![]() 4Aerospace and Mechanical Engineering, University of Arizona, Tucson, AZ, United States.3College of Animal Science and Technology, Northwest A&F University, Yangling, China.2Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ, United States.1School of Pharmacy, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou, China.Bi Liu 1,2 †, Xia Wang 2,3 †, Linan Jiang 4*, Jianhua Xu 1, Yitshak Zohar 4 and Guang Yao 2*
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