Abstract
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 antagonism originating from the organoid stromal core. PT-enhanced organoids represent an improved model to study inherited and acquired proximal tubular disease as well as drug and viral responses.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
1) Inclusion of more in-depth comparisons of standard and PT-enhanced organoids at the level of transcription, protein expression, functional transport capacity, application to nephrotoxicity assessment, and application to SARS-CoV-2 infection modelling. 2) Further clarification of PT-enhanced organoid non-nephron cell types 3) Quantification and further validation of existing data (mechanism of nephron spatial arrangement and SARS-CoV-2 experiments).