Abstract
Human pluripotent stem cell-derived kidney organoids have demonstrated utility in modeling kidney development and genetic disease. Autosomal recessive polycystic kidney disease (ARPKD) is an inherited developmental cystic kidney disease of high morbidity and mortality that lacks directed therapy. To overcome the limitations of animal models and stimulate drug discovery, ARPKD organoids have previously been subject to well-described cystogenic mechanisms for use in therapeutic screens. Although these studies have validated genotype-phenotype correlations and cystogenic response of ARPKD organoids as similar to existing in vitro models, novel cystogenic mechanisms that expand potential therapeutic targets have yet to be uncovered. Here we use a combination of human induced pluripotent stem cell-derived ARPKD and isogenic wild-type organoids, native kidney and organoid single-cell RNA sequencing, decedent human ARPKD tissue, and targeted mechanistic studies to describe PTH1R as a stimulatory G-protein-coupled receptor, which instigates a cystogenic signaling cascade in developmental cystic kidney disease. Our findings demonstrate the utility of kidney organoids as an in vitro model for pathomechanisms of rare diseases, which lack faithful animal models.NEW & NOTEWORTHY Stem cell-derived kidney organoids enable human genetic disease modeling to identify the parathyroid hormone 1 receptor as a potential new therapeutic target for developmental polycystic kidney disease.
Keywords:
PTH receptor; PTH signaling; human stem cell; kidney organoid; polycystic kidney disease.