Mechanical Tension Promotes Formation of Gastrulation-like Nodes and Patterns Mesoderm Specification in Human Embryonic Stem Cells

Muncie, Jonathon M.; Ayad, Nadia; Lakins, Johnathon N.; Xue, Xufeng; Fu, Jianping; Weaver, Valerie M.

doi:10.1016/j.devcel.2020.10.015

Cited by 97 publications

(99 citation statements)

References 84 publications

(131 reference statements)

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“…Discussion. In this paper, we have argued that mechanical stress may act like a morphogen, patterning cell fates in a position-dependent manner, in some hPS cell systems [44][45][46][47]. In particular, we find experimentally that the width of the NPB fate domain in our colonies depends non-monotonically on the substrate stiffness, as predicted by a model with a mechanical morphogen.…”

supporting

confidence: 54%

Generation of fate patterns via intercellular forces

Nunley

Xue

et al. 2021

Preprint

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Studies of fate patterning during development typically emphasize cell-cell communication via diffusible signals. Recent experiments on monolayer stem cell colonies, however, suggest that mechanical forces between cells may also play a role. These findings inspire a model of mechanical patterning: fate affects cell contractility, and pressure in the cell layer biases fate. Cells at the colony boundary, more contractile than cells at the center, seed a pattern that propagates via force transmission. In agreement with previous observations, our model implies that the width of the outer fate domain depends only weakly on colony diameter. We further predict and confirm experimentally that this same width varies non-monotonically with substrate stiffness. This finding supports the idea that mechanical stress can mediate patterning in a manner similar to a morphogen; we argue that a similar dependence on substrate stiffness can be achieved by a chemical signal only if strong constraints on the signaling pathway’s mechanobiology are met.

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supporting

confidence: 54%

Generation of fate patterns via intercellular forces

Nunley

Xue

et al. 2021

Preprint

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“…Organoids have often been used as simplified models of patterning and have allowed insight into the underlying biochemical [41][42][43][44] and mechanical 1,20,45,46 factors that control cell fate specification and morphogenesis. We and others have shown that NTOs display patterned FPs 9,11,12,20 which emerge, remarkably, despite the lack of the notochord, which in vivo acts as a spatial reference frame for FP patterning 28,47,48 through the secretion of SHH morphogens.…”

Section: Discussionmentioning

confidence: 99%

Neuroepithelial organoid patterning is mediated by Wnt-driven Turing mechanism

Fattah

Grebeniuk

Salmon

et al. 2021

Preprint

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Cell patterning in epithelia is critical for the establishment of tissue function during development. The organization of patterns in these tissues is mediated by the interpretation of signals operating across multiple length scales. How epithelial tissues coordinate changes in cell identity across these length scales to orchestrate cellular rearrangements and fate specification remains poorly understood. Here, we use human neural tube organoids as model systems to interrogate epithelial patterning principles that guide domain specification. In silico modeling of the patterning process by cellular automata, validated by in vitro experiments, reveal that the initial positions of floor plate cells, coupled with activator-inhibitor signaling interactions, deterministically dictate the patterning outcome according to a discretized Turing reaction-diffusion mechanism. This model predicts an enhancement of organoid patterning by modulating inhibitor levels. Receptor-ligand interaction analysis of scRNAseq data from multiple organoid domains reveals WNT-pathway ligands as the specific inhibitory agents, thereby allowing for the experimental validation of model predictions. These results demonstrate that neuroepithelia employ reaction-diffusion-based mechanisms during early embryonic human development to organize cellular identities and morphogen sources to achieve patterning. The wider implementation of such in vitro organoid models in combination with in-silico agent-based modeling coupled to receptor-ligand analysis of scRNAseq data opens avenues for a broader understanding of dynamic tissue patterning processes.

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“…However, it is difficult to separate the effect of tissue geometry and that of matrix stiffness on cells cultured in 3D. Indeed, direct force application (which could be linked to matrix stiffness) influences tissue geometry and the composition of the ECM ( Matsugaki et al, 2013 ; Muncie et al, 2020 ). Moreover, tumor proliferation and invasion are stimulated within a duct made of non-neoplastic epithelial cells only when mechanical stress is high, hence showing that mechanical stress acts independently on (or on top of) tissue geometry ( Boghaert et al, 2012 ).…”

Section: A Bright Future For 3d Cell Culture In Mechanomedicinementioning

confidence: 99%

3D Cell Culture for the Study of Microenvironment-Mediated Mechanostimuli to the Cell Nucleus: An Important Step for Cancer Research

Chhetri

Rispoli

Lelièvre

2021

Front. Mol. Biosci.

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The discovery that the stiffness of the tumor microenvironment (TME) changes during cancer progression motivated the development of cell culture involving extracellular mechanostimuli, with the intent of identifying mechanotransduction mechanisms that influence cell phenotypes. Collagen I is a main extracellular matrix (ECM) component used to study mechanotransduction in three-dimensional (3D) cell culture. There are also models with interstitial fluid stress that have been mostly focusing on the migration of invasive cells. We argue that a major step for the culture of tumors is to integrate increased ECM stiffness and fluid movement characteristic of the TME. Mechanotransduction is based on the principles of tensegrity and dynamic reciprocity, which requires measuring not only biochemical changes, but also physical changes in cytoplasmic and nuclear compartments. Most techniques available for cellular rheology were developed for a 2D, flat cell culture world, hence hampering studies requiring proper cellular architecture that, itself, depends on 3D tissue organization. New and adapted measuring techniques for 3D cell culture will be worthwhile to study the apparent increase in physical plasticity of cancer cells with disease progression. Finally, evidence of the physical heterogeneity of the TME, in terms of ECM composition and stiffness and of fluid flow, calls for the investigation of its impact on the cellular heterogeneity proposed to control tumor phenotypes. Reproducing, measuring and controlling TME heterogeneity should stimulate collaborative efforts between biologists and engineers. Studying cancers in well-tuned 3D cell culture platforms is paramount to bring mechanomedicine into the realm of oncology.

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Mechanical Tension Promotes Formation of Gastrulation-like Nodes and Patterns Mesoderm Specification in Human Embryonic Stem Cells

Cited by 97 publications

References 84 publications

Generation of fate patterns via intercellular forces

Generation of fate patterns via intercellular forces

Neuroepithelial organoid patterning is mediated by Wnt-driven Turing mechanism

3D Cell Culture for the Study of Microenvironment-Mediated Mechanostimuli to the Cell Nucleus: An Important Step for Cancer Research

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