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Increased Wnt/β-catenin Signaling Allows Overcrowded Stem Cells to Self-renew

Review of "Volumetric Compression Induces Intracellular Crowding to Control Intestinal Organoid Growth via Wntβ-Catenin Signaling" from Cell Stem Cell by Stuart P. Atkinson

While extracellular cues can alter the physical properties of cells, such as stiffness and intracellular crowding, how signaling processes and physiological functionalities respond to these alterations remains relatively unexplored in mammalian cells [1, 2]. Researchers led by Ming Guo (Massachusetts Institute of Technology, Cambridge, MA, USA) knew that the self-renewing epithelium of the intestine undergoes mechanical stress deriving from the expansion of intestinal stem cells (ISCs) [3] and osmotic stress deriving from daily diet and digestion [4]; however, the impact of extracellular physical cues on the function of intestinal cells remained elusive. Now, the Guo team returns with a new study that demonstrates how cellular physical properties can promote ISC self-renewal by inducing intracellular crowding and maintaining an elevated response to Wnt ligands [5].

Li et al. evaluated the effects of extracellular physical/mechanical cues on ISCs resident within the mouse intestinal epithelium and intestinal organoids and discovered that this type of stimulation regulated growth characteristics by reducing cell size and modifying intracellular crowding to elevate Wnt/β-catenin signaling. While intracellular crowding varies according to the type of extracellular physical/mechanical cue employed (mechanical forces, matrix rigidity, and osmotic stress), this mechanism leads to the stabilization of the LRP6 signalosome in ISCs by modulating the equilibrium of LRP6-Axin binding. In turn, the LRP6 signalosome inhibits the degradation of β-catenin and prompts the significant enhancement of Wnt target gene expression. Through a subsequent study of this mechanism in intestinal organoids, the authors provided evidence that intracellular crowding and elevated Wnt/β-catenin signaling following osmotic and mechanical compression prompts the self-renewal of ISCs within organoids, leading to organoid expansion.

The authors hope that their studies linking extracellular physical cues with intracellular signaling through intracellular crowding will pave the way for studies into additional cellular signaling pathways and other cell lineage commitments, as well as the appreciation of this mechanism in other mouse tissues, such as the lung and liver, and also human tissue. Importantly, these findings may also significantly contribute to the design of optimized strategies for the expansion of both stem cells and organoids.

For more on how increased Wnt/β-catenin signaling allows overcrowded intestinal stem cells to self-renew, stay tuned to the Stem Cells Portal!


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  4. Overduin J, Tylee TS, Frayo RS, et al., Hyperosmolarity in the small intestine contributes to postprandial ghrelin suppression. American Journal of Physiology-Gastrointestinal and Liver Physiology 2014;306:G1108-G1116.
  5. Li Y, Chen M, Hu J, et al., Volumetric Compression Induces Intracellular Crowding to Control Intestinal Organoid Growth via Wnt/b-Catenin Signaling. Cell Stem Cell 2021;28:63-78.e7.