Epithelia prefer their ECM firm and easily digested

By engineering synthetic gels, Enemchukwu et al. identify extracellular matrix (ECM) properties that control epithelial development.

Epithelial cells arrange themselves into an assortment of tubes, ducts, sacs, and spheres. Researchers have used natural gels containing collagen and laminin to probe how the ECM shapes these structures. But scientists can’t manipulate the properties of these matrices to determine which factors are crucial for normal development.

Enemchukwu et al. developed synthetic polyethylene glycol gels whose biochemical and biophysical properties can be modulated. The researchers first tested the effect of altering polymer density, which dictates gel elasticity. At moderate gel stiffness, individual kidney cells proliferated to form spheres, with the cells’ apical surfaces facing a central lumen. The cells’ polarity was often reversed at low gel densities, however, and at high densities no spheres formed.

ECM proteins carrying RGD peptides stimulate integrins and help steer epithelial development. Increasing RGD levels in the gels enhanced the formation of hollow spheres with normal polarity.

Before clusters of epithelial cells can grow or extend protrusions, they need to clear space by dissolving the surrounding ECM. Enemchukwu et al. varied how susceptible the gels were to digestion by proteases and determined that enzyme-resistant ECM disrupted lumen formation and polarization. Thus, ECM with moderate elasticity, abundant RGD peptides, and at least a low level of digestibility promotes normal epithelial development. The researchers say their tunable gel system can be used to study morphogenesis in various normal and pathological contexts.