2024 Theses Doctoral

Fibers to Forms: Cellular Prestress of Extracellular Matrix Fibers Controls Nonlinear Morphogenetic Mechanics in The Looping Small Intestine

Durel, John F.

The characteristic loops of the small intestine arise during embryonic development from differential growth as the intestinal tube elongates against the constraint of its attached dorsal mesentery, which compresses the tube until it buckles into loops. The number and shape of loops are conserved for a given species and are predictable from tube and mesentery geometries and stiffnesses. Importantly, the mesentery readily accommodates a certain amount of stretch from the elongating tube before stiffening by several orders of magnitude and resisting further extension—thereby dictating how differential growth translates into buckling forces. While such constitutive nonlinearity is well appreciated in adult soft tissues, its determinants and consequences remain largely unexplored in buckling morphogenesis and embryogenesis as a whole.

In this work, we undertake to establish a mechanistic link between molecular control of cell behaviors and organ-scale buckling morphogenesis of the small intestine. Using pharmacological treatments, mechanical testing, image analysis of tissue microstructure, and computational modeling, we test the hypothesis that actomyosin contractility regulates mesentery constitutive nonlinearity and thereby organ-scale buckling of the small intestine through its effects on extracellular matrix recruitment.

Our findings suggest that highly contractile cells could act as a mechanical ‘clutch’, modulating the stiffening transition of the mesentery by compacting stiff matrix fibers that must be decompressed by applied forces before contributing to stretch resistance. However, we also find that low levels of contractility control the initial soft response of the mesentery through a mechanism largely independent of matrix fiber straightness and alignment. Despite the apparent simplicity of buckling from a mechanical standpoint, its underlying biological determinants are evidently quite complex.

The present study begins to unpack those intricate links between the molecular and biophysical aspects of buckling morphogenesis by revealing how cell forces and matrix organization interactively dictate tissue-scale mechanics during development in sometimes counterintuitive ways.