Human iPSC-derived renal collecting duct organoid model cystogenesis in ADPKD
Shin-Ichi Mae, Fumihiko Hattanda, Hiroyoshi Morita, Aya Nozaki, Naoko Katagiri, Hanako Ogawa, Kaori Teranaka, Yu Nishimura, Aoi Kudoh, Sanae Yamanaka, Kyoko Matsuse, Makoto Ryosaka, Akira Watanabe, Tomoyoshi Soga, Saori Nishio, Kenji Osafune
Abstract
In autosomal dominant polycystic kidney disease (ADPKD), renal cyst lesions predominantly arise from collecting ducts (CDs). However, relevant CD cyst models using human cells are lacking. Although previous reports have generated in vitro renal tubule cyst models from human induced pluripotent stem cells (hiPSCs), therapeutic drug candidates for ADPKD have not been identified. Here, by establishing expansion cultures of hiPSC-derived ureteric bud tip cells, an embryonic precursor that gives rise to CDs, we succeed in advancing the developmental stage of CD organoids and show that all CD organoids derived from PKD1 −/− hiPSCs spontaneously develop multiple cysts, clarifying the initiation mechanisms of cystogenesis. Moreover, we identify retinoic acid receptor (RAR) agonists as candidate drugs that suppress in vitro cystogenesis and confirm the therapeutic effects on an ADPKD mouse model in vivo . Therefore, our in vitro CD cyst model contributes to understanding disease mechanisms and drug discovery for ADPKD.