The development of an induced pluripotent stem cell derived organoid platform to inform regenerative therapies for chronic kidney disease. (360G-Wellcome-211851_Z_18_Z)

The establishment of a platform that recapitulates the developmental process of renal organogenesis will increase our understanding of human development, while serving as a model for renal disease and pharmacological and toxicological studies. Importantly, organoids contain all components of the kidney and can thus be utilised for the study of each distinct cell type present, providing an exciting opportunity when combined with the power of scRNA-Seq and gene; tools such as the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system have been successfully used to generate specific genetic mutations in iPSC lines and single cell approaches will be used to map phenotypic trajectories in response to pathogenically relevant stimuli. Current protocols for the derivation of organoids have their limitations, and are likely to benefit from further improvements most notably a better understanding of the chromatin landscape during specification of individual cell types which will aid efforts towards achieving functional maturation. Indeed our preliminary data has demonstrated for the first time a method that facilitates the production of ZO-1+ve, CDH1+ve cells from iPSCs through manipulation of a Smad3-EZH2 switch and the establishment of a permissive chromatin state. Using this approach in organoids will likely increase their ability to reach maturation.