biostudies-literatureVanslambrouck JMNIDDK NIH HHSVictorian State Government | Department of Jobs, Precincts, and RegionsDepartment of Health | National Health and Medical Research CouncilU.S. Department of Health & Human Services | National Institutes of Health5943https://www.ebi.ac.uk/biostudies/studies/S-EPMC9547573biostudies-literatureUnknown13(1)While pluripotent stem cell-derived kidney organoids are now being used to model renal disease, the proximal nephron remains immature with limited evidence for key functional solute channels. This may reflect early mispatterning of the nephrogenic mesenchyme and/or insufficient maturation. Here we show that enhanced specification to metanephric nephron progenitors results in elongated and radially aligned proximalised nephrons with distinct S1 - S3 proximal tubule cell types. Such PT-enhanced organoids possess improved albumin and organic cation uptake, appropriate KIM-1 upregulation in response to cisplatin, and improved expression of SARS-CoV-2 entry factors resulting in increased viral replication. The striking proximo-distal orientation of nephrons resulted from localized WNT antagonisNature communicationsEnhanced metanephric specification to functional proximal tubule enables toxicity screening and infectious disease modelling in kidney organoids.PMC9547573UH3DK107344GNT1136085UH3 DK107344GNT1156440Groenewegen ELittle MHTan KSLawlor KTHowden SEScurr MSubbarao KWilson SBRudraraju RMah SNeil JVanslambrouck JMfalseEnhanced metanephric specification to functional proximal tubule enables toxicity screening and infectious disease modelling in kidney organoids.While pluripotent stem cell-derived kidney organoids are now being used to model renal disease, the proximal nephron remains immature with limited evidence for key functional solute channels. This may reflect early mispatterning of the nephrogenic mesenchyme and/or insufficient maturation. Here we show that enhanced specification to metanephric nephron progenitors results in elongated and radially aligned proximalised nephrons with distinct S1 - S3 proximal tubule cell types. Such PT-enhanced organoids possess improved albumin and organic cation uptake, appropriate KIM-1 upregulation in response to cisplatin, and improved expression of SARS-CoV-2 entry factors resulting in increased viral replication. The striking proximo-distal orientation of nephrons resulted from localized WNT antagonis2022-01-01T00:00:00Z2022 Oct2026-06-01T02:10:47.132Z2025-02-19T01:28:22.224ZS-EPMC95475733620921210.1038/s41467-022-33623-z