Modeling perspectives on the intestinal crypt, a canonical system for growth, mechanics, and remodeling

Almet, Axel A.; Maini, Philip K.; Moulton, Derek E.; Byrne, Helen M.

doi:10.1016/j.cobme.2019.12.012

Cited by 24 publications

(20 citation statements)

References 44 publications

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“…By contrast, how the crypt folds during morphogenesis and how folding is maintained during homeostasis is not well understood. Candidate folding mechanisms include buckling as a consequence of either increased mitotic pressure [12][13][14][15] , differentials in actomyosin forces between epithelial compartments 16 , or planar cellular flows 17 . Additionally, crypt folding could arise from bending by apical constriction 18,19 , basal expansion 20 or transepithelial differences in osmotic pressure 21,22 .…”

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confidence: 99%

“…The observed traction patterns and monolayer geometry can be explained by two classes of folding mechanisms. The first class relies on differentials in mitotic pressure [12][13][14] , which can induce a buckling instability that pushes the stem cell compartment towards the substrate. A second class is based on differentials in myosin contractility, either across the monolayer plane 16 or along the apicobasal axis [18][19][20] .…”

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confidence: 99%

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Mechanical compartmentalization of the intestinal organoid enables crypt folding and collective cell migration

et al. 2021

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Intestinal organoids capture essential features of the intestinal epithelium such as crypt folding, cellular compartmentalization and collective movements. Each of these processes and their coordination require patterned forces that are currently unknown. Here we map three-dimensional cellular forces in mouse intestinal organoids grown on soft hydrogels. We show that these organoids exhibit a non-monotonic stress distribution that defines mechanical and functional compartments. The stem cell compartment pushes the ECM and folds through apical constriction, whereas the transit amplifying zone pulls the ECM and elongates through basal constriction. The size of the stem cell compartment depends on ECM stiffness and endogenous cellular forces. Computational modeling reveals that crypt shape and force distribution rely on cell surface tensions following cortical actomyosin density. Finally, cells are pulled out of the crypt along a gradient of increasing tension. Our study unveils how patterned forces enable compartmentalization, folding and collective migration in the intestinal epithelium.

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confidence: 99%

Mechanical compartmentalization of the intestinal organoid enables crypt folding and collective cell migration

et al. 2021

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“…They have the advantage that they can be developed with a long-term view; if computational capacities are improved, further questions can be addressed based on the same model or straightforward model extensions. Exploiting these capabilities, computational tissue models have strongly supported the understanding of fate control of intestinal SCs in the last decade [ 42 ]. Here, we introduce an individual cell-based model of postnatal intestinal growth that builds on our previous models of the adult intestinal crypt [ 36 , 43 ] and intestinal organoids [ 16 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

How to Obtain a Mega-Intestine with Normal Morphology: In Silico Modelling of Postnatal Intestinal Growth in a Cd97-Transgenic Mouse

Hofmann

Thalheim

Rother

et al. 2021

IJMS

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Intestinal cylindrical growth peaks in mice a few weeks after birth, simultaneously with crypt fission activity. It nearly stops after weaning and cannot be reactivated later. Transgenic mice expressing Cd97/Adgre5 in the intestinal epithelium develop a mega-intestine with normal microscopic morphology in adult mice. Here, we demonstrate premature intestinal differentiation in Cd97/Adgre5 transgenic mice at both the cellular and molecular levels until postnatal day 14. Subsequently, the growth of the intestinal epithelium becomes activated and its maturation suppressed. These changes are paralleled by postnatal regulation of growth factors and by an increased expression of secretory cell markers, suggesting growth activation of non-epithelial tissue layers as the origin of enforced tissue growth. To understand postnatal intestinal growth mechanistically, we study epithelial fate decisions during this period with the use of a 3D individual cell-based computer model. In the model, the expansion of the intestinal stem cell (SC) population, a prerequisite for crypt fission, is largely independent of the tissue growth rate and is therefore not spontaneously adaptive. Accordingly, the model suggests that, besides the growth activation of non-epithelial tissue layers, the formation of a mega-intestine requires a released growth control in the epithelium, enabling accelerated SC expansion. The similar intestinal morphology in Cd97/Adgre5 transgenic and wild type mice indicates a synchronization of tissue growth and SC expansion, likely by a crypt density-controlled contact inhibition of growth of intestinal SC proliferation. The formation of a mega-intestine with normal microscopic morphology turns out to originate in changes of autonomous and conditional specification of the intestinal cell fate induced by the activation of Cd97/Adgre5.

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“…When it comes to computational models of crypt budding, they have been confined to the study of the healthy case of crypt fission. This is partly because validation of mathematical models of the crypt is particularly difficult, either due to the lack of experimental data or the difficulty to measure certain model parameters 49 , 50 . Notably, recent studies of crypt budding relate the spatial concentration of proteins (including the APC, β-catenin, E-cadherin and survivin) and cell proliferation and differentiation (including stem and mucus-secreting cells) with the crypt budding process 51 – 53 .…”

Section: Validation Of the 3d Cyclorama Methodsmentioning

confidence: 99%

3D cyclorama for digital unrolling and visualisation of deformed tubes

Rossides

Pender

Schneider

2021

Sci Rep

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Colonic crypts are tubular glands that multiply through a symmetric branching process called crypt fission. During the early stages of colorectal cancer, the normal fission process is disturbed, leading to asymmetrical branching or budding. The challenging shapes of the budding crypts make it difficult to prepare paraffin sections for conventional histology, resulting in colonic cross sections with crypts that are only partially visible. To study crypt budding in situ and in three dimensions (3D), we employ X-ray micro-computed tomography to image intact colons, and a new method we developed (3D cyclorama) to digitally unroll them. Here, we present, verify and validate our ‘3D cyclorama’ method that digitally unrolls deformed tubes of non-uniform thickness. It employs principles from electrostatics to reform the tube into a series of onion-like surfaces, which are mapped onto planar panoramic views. This enables the study of features extending over several layers of the tube’s depth, demonstrated here by two case studies: (i) microvilli in the human placenta and (ii) 3D-printed adhesive films for drug delivery. Our 3D cyclorama method can provide novel insights into a wide spectrum of applications where digital unrolling or flattening is necessary, including long bones, teeth roots and ancient scrolls.

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Modeling perspectives on the intestinal crypt, a canonical system for growth, mechanics, and remodeling

Cited by 24 publications

References 44 publications

Mechanical compartmentalization of the intestinal organoid enables crypt folding and collective cell migration

Mechanical compartmentalization of the intestinal organoid enables crypt folding and collective cell migration

How to Obtain a Mega-Intestine with Normal Morphology: In Silico Modelling of Postnatal Intestinal Growth in a Cd97-Transgenic Mouse

3D cyclorama for digital unrolling and visualisation of deformed tubes

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