The art of folding tissues: the small bowel villi origami guide

Huycke T, Häkkinen T, Miyazaki H, et al. Patterning and folding of intestinal villi by active mesenchymal dewetting. Cell 2024; 187(12): 3072-3089.e20. doi: 10.1016/j.cell.2024.04.039.

Tissues folding is fundamental for specific organ function. Small intestine villi form by curvature of interface of mesenchymal–epithelium in foetus, where folding occurs in the presence of platelets-derived grown factor receptor alpha (PDGFRA) cells. In this paper, Huycke et al, explored drivers of this process.

By performing long-term time-elapse experiment in vitro, Huycke et al, noted epithelial curvature and PDGFRA^high aggregates occurred simultaneously. De-epithelised models, treated with Hedgehog ligand agonist, displayed both mesenchymal aggregation and tissue folding in PDGFRA^high tissues. Single-cell RNA analysis identified PDGFRA^high cells were located in subepithelium and expressed adhesional and cell-extracellular matrix interactions properties. The role of non-muscle myosin in folding was investigated by treating tissues with blebbistatin (an inhibitor): PDGFRA^high failed to move, aggregate or initiate curvature of tissues. By measuring recoil of damaged subepithelial layers along de-epithelised intestine, Huycke et al, demonstrate how loss of tensile stresses proximally induced repair by forming aggregates. Those aggregates show fluid-like characteristics. PDGFRA^high tissue showed increased motility, droplets formation and high surface tension when in contact with PDGFRA^low tissue. Thus, PDGFRA^high aggregate surfaced near the epithelium. Inhibition of metalloproteinase caused lack of mesenchymal aggregates’ formation. Using Cahn-Hilliard models, Huycke et al, demonstrated both high tension between tissues and thickness of the PDGFRA^high cell layer were fundamental for villus formation. When tissue was treated with ITGA2B1 (integrin alpha 2 beta 1) inhibitor to reduce cohesivity, aggregates did not form nor surface to the epithelium.

These findings suggest villi folding is directly dependent to PDGFRA^high cell aggregates forming when tissues transition from solid to fluid-like mediated by extracellular matrix and tissue surface tensions. …