1/11 In @ScienceMagazine: A new perspective on how our intestines renew. Cells are not “pushed out” by crowding or die from apoptosis. Instead, cells play a mechanical tug-of-war, where weaker cells extrude, reframing gut renewal as force-regulated. https://www.science.org/doi/10...
2/11 The intestinal lining renews every few days. Old cells are shed by extrusion—a process essential for barrier integrity and linked to diseases like IBD. But what actually triggers extrusion in mammals was unclear.
3/11 Using long-term live imaging & tracking (by @_amolf), we followed hundreds of extrusion events. Most villus cells extruded alive, not apoptotic. Extrusion did not correlate with density.
4/11 Are villus tips - where extrusion peaks -compressed by crowding? @_Hubrecht , laser ablation revealed they are under tension, not compression. That tension sets the stage for extrusion.
5/11 Using CRISPR-generated myosin reporters, we first observed myosin increasing in extruding cells, together with a synchronized response in their neighbors - explaining extrusion dynamics as a coordinated process.
6/11 A basal actomyosin network generates epithelial tension. On hydrogel substrates that mimic the in vivo villus topology (generated by @IHB_Research) we saw pulsatile contractions—one cell contracts, neighbors expand. A tissue-wide tug-of-war.
7/11 Optogenetics let us induce contractility with blue light and spatial precision. Extrusion rates jumped up upon activation, showing that globally increased tension directly drives extrusion.
8/11 Local photoactivation on villus substrates, creating boundaries between highly- & less-contractile cells caused preferential extrusion on the weaker side. In mosaic organoids, less contractile "weaker" cells were consistently eliminated. Are weak cells primed for extrusion?
9/11 With point ablations at the base, we intentionally weakened individual cells. Within minutes, these cells extruded - loss of tension likely triggers extrusion.
10/11 Disease link: In EpCAM loss (tufting enteropathy), hyperactive myosin caused excessive extrusion, growth defects, and tissue disruption. Too much force destabilizes the barrier. Mixing mutant & WT cells made healthy cells extrude. Myosin inhibition rescued this effect.
11/11 Take-home: Gut homeostasis is not passive crowd control. It’s an active, force-regulated process. Cells constantly test each other’s strength; those that fail the tug-of-war extrude. A collaboration between the @_Hubrecht, @_amolf & @IHB_Research lead by @DanielKruegerDK
@HansClevers @ScienceMagazine Fascinating shift in perspective—seeing renewal as force-regulated really reframes how we think about intestinal health. Do you think this could open new doors for targeting epithelial tension in disease treatment?
@HansClevers @ScienceMagazine Beautiful work. Congratulations!
@HansClevers @ScienceMagazine Bu da bizden olsun https://youtu.be/814fr-UBvik?s...