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However, human pluripotent stem cell\u2010derived kidney organoids do not incorporate UB differentiation, limiting organoid maturation and disease modeling. Here, a hypoxia\u2010based differentiation method inspired by developmental cues is reported that produces mature kidney organoids with collecting duct\u2010like tubules connected to multiple nephrons. Hypoxia promotes the co\u2010induction of MM and UB\u2010like progenitors within the same culture dish. The augmented expression of reciprocal signaling genes guides the differentiation of the kidney organoids into highly structured tubular networks, mature RNA profiles, and a more realistic micro\u2010anatomy, leading to higher\u2010order kidney organogenesis in vitro. These hypoxia\u2010enhanced kidney organoids recapitulate the cystic phenotype in polycystic kidney disease, displaying efficient cyst formation across the entire tubular region and increased sensitivity to drugs. The findings provide an improved in vitro model for studying kidney development and disease mechanisms.<\/jats:p>","DOI":"10.1002\/advs.202501661","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T03:43:50Z","timestamp":1755834230000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Developmental Hypoxia Enhances Kidney Organoid Complexity and Maturity"],"prefix":"10.1002","volume":"12","author":[{"given":"Hyeonji","family":"Lim","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering College of Information\u2010Bio Convergence Engineering Ulsan National Institute of Science and Technology (UNIST)  Ulsan 44919 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dohui","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering Pohang University of Science and Technology (POSTECH)  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