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.
Highlights
Current kidney organoids model development and diseases of the nephron but not the contiguous epithelial network of the kidney’s collecting duct (CD) system
UB progenitor cells (UPCs) disappear around postnatal Day 2 (P2), when nephrogenesis ceases
Ret[31,32] and Wnt1133 have been identified as specific markers for UPCs and regulate UPC programs directly (Ret) or through feedback mechanisms (Wnt11)
Summary
Current kidney organoids model development and diseases of the nephron but not the contiguous epithelial network of the kidney’s collecting duct (CD) system. 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. We and others have been able to generate kidney organoids from human pluripotent stem cells (hPSCs)[8,9,10,11] or from expandable nephron progenitor cells (NPCs)[12,13,14] These organoids have greatly aided studies of the role of nephrons in kidney development and disease[15]. UB organoids derived from either primary UB progenitor cells or hPSCs are amenable to efficient gene editing, and have broad applications for studying kidney development, regeneration, and disease
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