Generation of patterned kidney organoids that recapitulate the adult kidney collecting duct system from expandable ureteric bud progenitors

TLDR

Current kidney organoids model nephron development and disease but lack the contiguous epithelial network of the kidney’s collecting duct system. The study aims to generate an expandable, 3D branching ureteric bud organoid culture model derived from primary progenitors of mouse and human fetal kidneys or from human pluripotent stem cells. This model is established by culturing ureteric bud progenitors in a chemically defined 3D environment that supports branching morphogenesis. UB organoids cultured in defined conditions differentiate into collecting duct organoids with spatially organized principal and intercalated cells, support branching morphogenesis and nephron induction when combined with nephron progenitors, and, upon RET deletion, recapitulate congenital kidney anomalies, thereby providing a versatile platform for studying collecting duct development, regeneration, and disease.

Abstract

Abstract Current kidney organoids model development and diseases of the nephron but not the contiguous epithelial network of the kidney’s collecting duct (CD) system. Here, we report the generation of an expandable, 3D branching ureteric bud (UB) organoid culture model that can be derived from primary UB progenitors from mouse and human fetal kidneys, or generated de novo from human pluripotent stem cells. In chemically-defined culture conditions, UB organoids generate CD organoids, with differentiated principal and intercalated cells adopting spatial assemblies reflective of the adult kidney’s collecting system. Aggregating 3D-cultured nephron progenitor cells with UB organoids in vitro results in a reiterative process of branching morphogenesis and nephron induction, similar to kidney development. Applying an efficient gene editing strategy to remove RET activity, we demonstrate genetically modified UB organoids can model congenital anomalies of kidney and urinary tract. Taken together, these platforms will facilitate an enhanced understanding of development, regeneration and diseases of the mammalian collecting duct system.