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Background  DNA variants in  APOL1  associate with kidney disease, but the pathophysiologic mechanisms remain incompletely understood. Model organisms lack the  APOL1  gene, limiting the degree to which disease states can be recapitulated. Here we present single-cell RNA sequencing (scRNA-seq) of genome-edited human kidney organoids as a platform for profiling effects of  APOL1  risk variants in diverse nephron cell types.    Methods  We performed footprint-free CRISPR-Cas9 genome editing of human induced pluripotent stem cells (iPSCs) to knock in  APOL1  high-risk G1 variants at the native genomic locus. iPSCs were differentiated into kidney organoids, treated with vehicle, IFN- γ , or the combination of IFN- γ  and tunicamycin, and analyzed with scRNA-seq to profile cell-specific changes in differential gene expression patterns, compared with isogenic G0 controls.    Results  Both G0 and G1 iPSCs differentiated into kidney organoids containing nephron-like structures with glomerular epithelial cells, proximal tubules, distal tubules, and endothelial cells. Organoids expressed detectable  APOL1  only after exposure to IFN- γ . scRNA-seq revealed cell type–specific differences in G1 organoid response to  APOL1  induction. Additional stress of tunicamycin exposure led to increased glomerular epithelial cell dedifferentiation in G1 organoids.    Conclusions  Single-cell transcriptomic profiling of human genome-edited kidney organoids expressing  APOL1  risk variants provides a novel platform for studying the pathophysiology of APOL1-mediated kidney disease.

Profiling APOL1 Nephropathy Risk Variants in Genome-Edited Kidney Organoids with Single-Cell Transcriptomics