Extracellular Fluid Flow Induces Shallow Quiescence Through Physical and Biochemical Cues

Bi Liu, Xia Wang, Linan Jiang, Jianhua Xu, Yitshak Zohar, Guang Yao

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number792719
JournalFrontiers in Cell and Developmental Biology
Volume10
DOIs
StatePublished - Feb 24 2022

Keywords

  • cellular quiescence
  • extracellular factors
  • extracellular fluid flow
  • flow shear stress
  • mathematical model
  • microenvironment
  • microfluidics
  • quiescence depth

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

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