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Spatial constraints control cell proliferation in tissues

  1. Lars Hufnagelb,2
  1. aKavli Institute for Theoretical Physics, University of California, Santa Barbara, CA 93106;
  2. bCell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany; and
  3. cDepartment of Biology, Stanford University, Stanford, CA 94305

  1. Edited by Robert H. Austin, Princeton University, Princeton, NJ, and approved February 28, 2014 (received for review December 11, 2013)

Significance

Spatiotemporal coordination of cell growth underlies tissue development and disease. Mechanical feedback between cells has been proposed as a regulatory mechanism for growth control both in vivo and in cultured cells undergoing contact inhibition of proliferation. Evidence beyond theoretical and correlative observations falls short. In this study, we probe the impact of mechanical tissue perturbations on cell cycle progression by monitoring cell cycle dynamics of cells in tissues subject to acute changes in boundary conditions, as well as tissue stretching and compression. Taken together, we conclude that the ability of tissues to support cell cycle progression adapts to the available space through a memory-free control mechanism, which may coordinate proliferation patterns to maintain tissue homeostasis.

Abstract

Control of cell proliferation is a fundamental aspect of tissue formation in development and regeneration. Cells experience various spatial and mechanical constraints depending on their environmental context in the body, but we do not fully understand if and how such constraints influence cell cycle progression and thereby proliferation patterns in tissues. Here, we study the impact of mechanical manipulations on the cell cycle of individual cells within a mammalian model epithelium. By monitoring the response to experimentally applied forces, we find a checkpoint at the G1–S boundary that, in response to spatial constraints, controls cell cycle progression. This checkpoint prevents cells from entering S phase if the available space remains below a characteristic threshold because of crowding. Stretching the tissue results in fast cell cycle reactivation, whereas compression rapidly leads to cell cycle arrest. Our kinetic analysis of this response shows that cells have no memory of past constraints and allows us to formulate a biophysical model that predicts tissue growth in response to changes in spatial constraints in the environment. This characteristic biomechanical cell cycle response likely serves as a fundamental control mechanism to maintain tissue integrity and to ensure control of tissue growth during development and regeneration.

Footnotes

  • ↵1S.J.S. and C.R.H. contributed equally to this work.

  • ↵2To whom correspondence may be addressed. E-mail: streicha{at}kitp.ucsb.edu or hufnagel{at}embl.de.

  • Author contributions: S.J.S. and L.H. designed research; S.J.S., C.R.H., and T.S. performed research; S.J.S. and D.H. contributed new reagents/analytic tools; S.J.S. and C.R.H. analyzed data; and S.J.S., C.R.H., and L.H. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1323016111/-/DCSupplemental.

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