Capturing the mechanosensitivity of cell proliferation in models of epithelium

Titelangaben

Höllring, Kevin ; Nuić, Lovro ; Rogić, Luka ; Kaliman, Sara ; Gehrer, Simone ; Wollnik, Carina ; Rehfeldt, Florian ; Hubert, Maxime ; Smith, Ana-Sunčana:
Capturing the mechanosensitivity of cell proliferation in models of epithelium.
In: Proceedings of the National Academy of Sciences of the United States of America. Bd. 121 (Oktober 2024) Heft 45 . - e2308126121.
ISSN 1091-6490
DOI: https://doi.org/10.1073/pnas.2308126121

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Abstract

This paper investigates the role of cellular interactions and the surrounding matrix on cell proliferation in a simple epithelium. The synergistic effect of both factors yields a nonlinear dependence of proliferation probability on cell density and matrix stiffness. These experimental findings are rationalized by theoretical modeling where the probability of proliferation could be related to the mechanoresponsiveness of individual cells. By integrating these results into simulations and numerical calculations, it was shown that mechanosensitivity of proliferation can significantly affect the development of model tissue. Overall, this study provides valuable insights into the mechanical signals underlying cell proliferation. The findings may have important implications for the development of therapeutic strategies for tissue repair, regeneration, and maintenance of homeostasis. Despite the primary role of cell proliferation in tissue development and homeostatic maintenance, the interplay between cell density, cell mechanoresponse, and cell growth and division is not yet understood. In this article, we address this issue by reporting on an experimental investigation of cell proliferation on all time- and length-scales of the development of a model tissue, grown on collagen-coated glass or deformable substrates. Through extensive data analysis, we demonstrate the relation between mechanoresponse and probability for cell division, as a function of the local cell density. Motivated by these results, we construct a minimal model of cell division in tissue environment that can recover the data. By parameterizing the growth and the dividing phases of the cell cycle, and introducing such a proliferation model in dissipative particle dynamics simulations, we recover the mechanoresponsive, time-dependent density profiles in 2D tissues growing to macroscopic scales. The importance of separating the cell population into growing and dividing cells, each characterized by a particular time scale, is further emphasized by calculations of density profiles based on adapted Fisher–Kolmogorov equations. Together, these results show that the mechanoresponse on the level of a constitutive cell and its proliferation results in a matrix-sensitive active pressure. The latter evokes massive cooperative displacement of cells in the invading tissue and is a key factor for developing large-scale structures in the steady state.