Volumetric Compression Induces Intracellular Crowding to Control Intestinal Organoid Growth via Wnt/β-Catenin Signaling

• Published in: Cell stem cell Vol. 28; no. 1; pp. 63 - 78.e7
• Main Authors: Li, Yiwei, Chen, Maorong, Hu, Jiliang, Sheng, Ren, Lin, Qirong, He, Xi, Guo, Ming
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.01.2021
• Subjects: beta Catenin - metabolism; biophysics; cell mechanics; Cell Self Renewal; cell volume; LRP6 signalosome; mechanobiology; molecular crowding; organoid; Organoids - metabolism; stem cell; Stem Cells - metabolism; volumetric compression; Wnt Signaling Pathway; Wnt/β-catenin signaling; mechanobiology; Wnt/β-catenin signaling; cell volume; stem cell; volumetric compression; cell mechanics; molecular crowding; LRP6 signalosome; biophysics; organoid
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2020.09.012

Enormous amounts of essential intracellular events are crowdedly packed inside picoliter-sized cellular space. However, the significance of the physical properties of cells remains underappreciated because of a lack of evidence of how they affect cellular functionalities. Here, we show that volumetric compression regulates the growth of intestinal organoids by modifying intracellular crowding and elevating Wnt/β-catenin signaling. Intracellular crowding varies upon stimulation by different types of extracellular physical/mechanical cues and leads to significant enhancement of Wnt/β-catenin signaling by stabilizing the LRP6 signalosome. By enhancing intracellular crowding using osmotic and mechanical compression, we show that expansion of intestinal organoids was facilitated through elevated Wnt/β-catenin signaling and greater intestinal stem cell (ISC) self-renewal. Our results provide an entry point for understanding how intracellular crowdedness functions as a physical regulator linking extracellular physical cues with intracellular signaling and potentially facilitate the design of engineering approaches for expansion of stem cells and organoids. [Display omitted] •Various physical cues regulate intracellular crowding via inducing volumetric compression•Molecular crowding as a mechanoregulator of Wnt/β-catenin signaling•Intracellular molecular crowding stabilizes LRP6 signalosome formation•Volumetric compression promotes self-renewal of intestinal stem cells in organoids Li et al. unveil the role of intracellular crowding in linking extracellular volumetric compression and cellular Wnt/β-catenin signaling via modulating LRP6 signalosome formation. They further extend these findings in settings of intestinal epithelium and organoids to elevating self-renewing of intestinal stem cells and growth of organoids.