Abstract
Ureteric bud (UB) is the embryonic kidney progenitor tissue that gives rise to the collecting duct and lower urinary tract. UB-like structures generated from human pluripotent stem cells by previously reported methods show limited developmental ability and limited branching. Here we report a method to generate UB organoids that possess epithelial polarity and tubular lumen and repeat branching morphogenesis. We also succeed in monitoring UB tip cells by utilizing the ability of tip cells to uptake very-low-density lipoprotein, cryopreserving UB progenitor cells, and expanding UB tip cells that can reconstitute the organoids and differentiate into collecting duct progenitors. Moreover, we successfully reproduce some phenotypes of multicystic dysplastic kidney (MCDK) using the UB organoids. These methods will help elucidate the developmental mechanisms of UB branching and develop a selective differentiation method for collecting duct cells, contributing to the creation of disease models for congenital renal abnormalities.
Highlights
The mammalian adult kidney, metanephros, develops by the reciprocal interaction between two embryonic progenitor tissues, metanephric mesenchyme and ureteric bud (UB) (Costantini and Kopan, 2010)
We manually separated the tips from the induced UB (iUB) organoids and cultured them in stage 6 medium (Figures S2A and S2B)
The tips separated from the reconstituted iUB organoids reconstituted iUB organoids with branching morphogenesis
Summary
The mammalian adult kidney, metanephros, develops by the reciprocal interaction between two embryonic progenitor tissues, metanephric mesenchyme and ureteric bud (UB) (Costantini and Kopan, 2010). Nephron progenitors (NPs) included in metanephric mesenchyme secrete glial cell-derived neurotrophic factor (GDNF) to maintain the proliferation and regulate the branching morphogenesis of UB cells and undergo a mesenchymal-to-epithelial transition to form nephron structures (Costantini and Kopan, 2010; Takahashi, 2001). In order to extend the findings and generate disease models for many CAKUT forms, the establishment of selective differentiation and expansion culture methods for CD lineage cells derived from hiPSCs and human embryonic stem cells (hESCs) is required
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