Spatial constraints control cell proliferation in tissues

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 15; pp. 5586 - 5591
• Main Authors: Streichan, Sebastian J., Hoerner, Christian R., Schneidt, Tatjana, Holzer, Daniela, Hufnagel, Lars
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 15.04.2014; National Acad Sciences
• Subjects: Animal cells; Animals; Biological Sciences; Biomechanical Phenomena; biomechanics; Biophysics; Cell cycle; cell cycle checkpoints; Cell Cycle Checkpoints - physiology; Cell growth; Cell lines; Cell Proliferation; Cells; Contact Inhibition - physiology; Cultured cells; Dogs; epithelium; Interphase; Kinetics; lymphocytes; Madin Darby Canine Kidney Cells; mammals; Modeling; Models, Biological; monitoring; Spatial models; spatial variation; Sprains and strains; Tissues; size checkpoint; mechanical feedback; cell cycle regulation; quantitative biology; G1-S transition
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1323016111

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.