Tubuloid as an alternative model of ADPKD

Human pluripotent stem cell (hPSC)–derived kidney organoids contain both segmentally patterned nephron epithelial structures and stromal cells, representing an exceptional tool for studying human kidney development and disease. However, hPSC-derived kidney organoids resemble first or second trimester kidneys and do not fully recapitulate adult kidney physiology. In comparison, organoids generated from adult kidney tissue primarily adopt 3-dimensional epithelial structures and express more mature epithelial cell markers. Increasing evidence supports the notion that the developmental stage of parental cells determines the maturation level of organoids in vitro. Hence, adult tissue–derived organoids may better reflect the characteristics of adult kidney tissue. Autosomal dominant polycystic kidney disease (ADPKD), caused primarily by mutations in PKD1 or PKD2, represents one of the most common human genetic diseases. PKD1−/− and PKD2−/− hPSC-derived kidney organoids primarily recapitulate proximal tubule (PT) cyst formation. Moreover, the fetal-like state and lack of collecting ducts preclude the use of these organoid models to represent the full spectrum of ADPKD phenotypes. Adult kidney tubular epithelial organoids, or “tubuloids,” have recently been derived from human kidney tissue and cells in urine as well as from kidney cancer tissue.4 Tubuloids contain both progenitor-like cells and epithelial cells expressing different nephron segment markers, but the cellular origin of tubuloids and their potential to model human genetic disease has not been investigated. In a recent study published in Nature Genetics, Xu et al. investigated the cellular origins of tubuloids and whether tubuloids can be used to model adult onset ADPKD