Patient-iPSC-derived kidney organoids show functional validation of a ciliopathic renal phenotype. Patient-iPSC-derived kidney organoids show functional validation of a ciliopathic renal phenotype

Purpose: A proof of concept study examining the disease modelling capabilities of patient iPSC derived kidney organoids. Methods: A proband was diagnosed by genome sequencing with compound heterozygous IFT140 mutations. A one-step reprogramming/gene-editing protocol of proband fibroblasts was used to derive both uncorrected patient and isogenic gene-corrected induced pluripotent stem cells (iPSC) which were differentiated to kidney organoids. Organoids were examined by immunofluorescence. Additionally, epithelial cells magnetically sorted from whole kidney organoids underwent transcriptional profiling and spheroid culture. Results: Differential expression analysis of organoid epithelial cell fractions demonstrated apicobasal polarity, cell-cell junction and dynein motor assembly downregulation in patient organoids. Defective ciliary morphology and spheroid culture were rescued in gene corrected organoids. Conclusions: This study validates patient iPSC-derived kidney organoids as a novel, faithful and patient-specific model to further the study of inherited renal disease in regenerated, human, in vitro tissue. Overall design: RNA-seq of three replicates each of uncorrected (IFT140 compound heterozygous) and gene-corrected (IFT140 heterozygous) the epithelial cells isolated from patient iPSC derived kidney organoids.