Mechanics defines the spatial pattern of compensatory proliferation

Abstract

The number of cells in tissues is tightly controlled by cell division and cell death, and misregulation of cell numbers could lead to pathological conditions such as cancer. To maintain cell numbers in a tissue, a cell elimination process named programmed cell death or apoptosis, stimulates the proliferation of neighboring cells. This mechanism is called apoptosis-induced compensatory proliferation, which was originally reported more than 40 years ago. While only a limited number of the neigboring cells need to divide to compensate for apoptotic cell loss, the mechanisms that select cells for undergoing division remain an open question. Here we found that the spatial inhomogeneity in mechanotransduction through a growth-promoting transcription co-activator Yes-associated protein (YAP) in the neighboring tissue, accounts for the inhomogeneity of compensatory proliferation. Such inhomogeneous mechanotransduction arises from the combination of the non-uniform distribution of nuclear size, which is inherent in tissues, and the non-uniform pattern of mechanical force applied to the neighboring cells upon apoptosis. Our findings from a mechanical perspective complement the current biochemical understanding of compensatory growth and provide additional insights into cellular functions of how tissue precisely maintains its homeostasis.

DeXtrusion: automatic recognition of epithelial cell extrusion through machine learning in vivo

“…DeXtrusion offers the possibility of screening for drugs or mutations affecting the spatiotemporal distribution of cell death and could lead to the identification of new biological factors modulating cell apoptosis and new spatiotemporal feedback mechanisms. We extended DeXtrusion to detect cell divisions and SOPs with the aim of improving our precision, but these additional features could also be useful for analysis of the spatiotemporal interplay between these three cellular events, for instance the coupling between cell death and cell division and compensatory proliferation ( Fan and Bergmann, 2008 ; Kawaue et al, 2021 preprint; Mesa et al, 2018 ). Combining such large datasets with graphical neural networks ( Yamamoto et al, 2022 ) and spatiotemporal point pattern analysis and modelling ( Valon et al, 2021 ) may eventually help to rapidly detect new spatiotemporal couplings at various xyt distances.…”

DeXtrusion: Automatic recognition of epithelial cell extrusion through machine learningin vivo

“…DeXtrusion offers the possibility for large screening of drugs/mutations on the spatiotemporal distribution of cell death that could lead to the identification of new biological factors modulating cell apoptosis and new spatiotemporal feedbacks. While we extended DeXtrusion to detect cell division and SOPs with the aim of improving our precision, these additional features can also be handy to analyse the spatiotemporal interplay between these three cellular events, for instance regarding the coupling between cell death and cell division (Fan and Bergmann, 2008; Kawaue et al, 2021; Mesa et al, 2018). Note however that we did not estimate the accuracy of our pipeline to detect these other cellular events as it was not the initial scope of our study.…”

Patterned apoptosis has an instructive role for local growth and tissue shape regulation in a fast-growing epithelium

“…Further work studying quantitatively the coupling between apoptosis and cell proliferation would be essential to assess its real contribution to physiological growth regulation. Interestingly, a recent study outlined a significant positive upregulation of proliferation near dying cell in MDCK cell, however this effect is strongly context dependent and is not visible at low stiffness or high density values[29], conditions that may apply to the wing imaginal disc.…”