3D Hydrogel Encapsulation Regulates Nephrogenesis in Kidney Organoids

Stem cell‐derived kidney organoids contain nephron segments that recapitulate morphological and functional aspects of the human kidney. However, directed differentiation protocols for kidney organoids are largely conducted using biochemical signals to control differentiation. Here, the hypothesis that mechanical signals regulate nephrogenesis is investigated in 3D culture by encapsulating kidney organoids within viscoelastic alginate hydrogels with varying rates of stress relaxation. Tubular nephron segments are significantly more convoluted in kidney organoids differentiated in encapsulating hydrogels when compared with those in suspension culture. Hydrogel viscoelasticity regulates the spatial distribution of nephron segments within the differentiating kidney organoids. Consistent with these observations, a particle‐based computational model predicts that the extent of deformation of the hydrogel–organoid interface regulates the morphology of nephron segments. Elevated extracellular calcium levels in the culture medium, which can be impacted by the hydrogels, decrease the glomerulus‐to‐tubule ratio of nephron segments. These findings reveal that hydrogel encapsulation regulates nephron patterning and morphology and suggest that the mechanical microenvironment is an important design variable for kidney regenerative medicine. Stem cell‐derived kidney organoid differentiation is largely conducted using biochemical signals to control cell differentiation. Here, the hypothesis that mechanical signaling regulates nephrogenesis in kidney organoids is investigated. 3D encapsulation of differentiating kidney organoids in viscoelastic alginate hydrogels alters nephron patterning and morphology. These findings suggest that mechanical signaling is an important consideration for kidney regenerative medicine.