Hydraulic resistance induces cell phenotypic transition in confinement

Runchen Zhao; Siqi Cui; Zhuoxu Ge; Yuqi Zhang; Kaustav Bera; Lily Zhu; Sean X Sun; Konstantinos Konstantopoulos

doi:10.1126/sciadv.abg4934

Hydraulic resistance induces cell phenotypic transition in confinement

Sci Adv. 2021 Apr 23;7(17):eabg4934. doi: 10.1126/sciadv.abg4934. Print 2021 Apr.

Authors

Runchen Zhao^{1

2}, Siqi Cui^{1

2}, Zhuoxu Ge^{2

3}, Yuqi Zhang^{1

2}, Kaustav Bera^{1

2}, Lily Zhu¹, Sean X Sun^{1

2

3

4

5}, Konstantinos Konstantopoulos^{6

2

4

5

7}

Affiliations

¹ Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
² Johns Hopkins Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.
³ Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
⁴ Johns Hopkins Physical Sciences-Oncology Center, Johns Hopkins University, Baltimore, MD 21218, USA.
⁵ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
⁶ Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA. konstant@jhu.edu.
⁷ Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA.

Abstract

Cells penetrating into confinement undergo mesenchymal-to-amoeboid transition. The topographical features of the microenvironment expose cells to different hydraulic resistance levels. How cells respond to hydraulic resistance is unknown. We show that the cell phenotype shifts from amoeboid to mesenchymal upon increasing resistance. By combining automated morphological tracking and wavelet analysis along with fluorescence recovery after photobleaching (FRAP), we found an oscillatory phenotypic transition that cycles from blebbing to short, medium, and long actin network formation, and back to blebbing. Elevated hydraulic resistance promotes focal adhesion maturation and long actin filaments, thereby reducing the period required for amoeboid-to-mesenchymal transition. The period becomes independent of resistance upon blocking the mechanosensor TRPM7. Mathematical modeling links intracellular calcium oscillations with actomyosin turnover and force generation and recapitulates experimental data. We identify hydraulic resistance as a critical physical cue controlling cell phenotype and present an approach for connecting fluorescent signal fluctuations to morphological oscillations.

Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Publication types

Research Support, N.I.H., Extramural

Abstract

Publication types

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