Linking stem cell function and growth pattern of intestinal organoids.


Intestinal stem cells (ISCs) require well-defined signals from their environment in order to carry out their specific functions. Most of these signals are provided by neighboring cells that form a stem cell niche, whose shape and cellular composition self-organize. Major features of this self-organization can be studied in ISC-derived organoid culture. In this system, manipulation of essential pathways of stem cell maintenance and differentiation results in well-described growth phenotypes. We here provide an individual cell-based model of intestinal organoids that enables a mechanistic explanation of the observed growth phenotypes. In simulation studies of the 3D structure of expanding organoids, we investigate interdependences between Wnt- and Notch-signaling which control the shape of the stem cell niche and, thus, the growth pattern of the organoids. Similar to in vitro experiments, changes of pathway activities alter the cellular composition of the organoids and, thereby, affect their shape. Exogenous Wnt enforces transitions from branched into a cyst-like growth pattern; known to occur spontaneously during long term organoid expansion. Based on our simulation results, we predict that the cyst-like pattern is associated with biomechanical changes of the cells which assign them a growth advantage. The results suggest ongoing stem cell adaptation to in vitro conditions during long term expansion by stabilizing Wnt-activity. Our study exemplifies the potential of individual cell-based modeling in unraveling links between molecular stem cell regulation and 3D growth of tissues. This kind of modeling combines experimental results in the fields of stem cell biology and cell biomechanics constituting a prerequisite for a better understanding of tissue regeneration as well as developmental processes.

PubMed ID: 29198564

Projects: ProstataCA

Publication type: Not specified

Journal: Dev Biol

Human Diseases: Colonic disease

Citation: Dev Biol. 2018 Jan 15;433(2):254-261. doi: 10.1016/j.ydbio.2017.10.013. Epub 2017 Nov 30.

Date Published: 15th Jan 2018

Registered Mode: by PubMed ID

Authors: T. Thalheim, M. Quaas, M. Herberg, U. D. Braumann, C. Kerner, M. Loeffler, G. Aust, J. Galle

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Views: 2621

Created: 29th Aug 2019 at 11:39

Last updated: 7th Dec 2021 at 17:58

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