Genome editing in kidney organoids
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ABSTRACT:
PROVIDER: PRJNA1207530 | ENA |
REPOSITORIES: ENA
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Project description:Genome editing has transformative potential for curing human diseases but poses unique challenges due to irreversible DNA alterations. Ensuring safe and effective in vivo editing requires preclinical studies to mitigate risks like genotoxicity, cytotoxicity, and immunogenicity. The kidney, highly susceptible to off-target effects due to its blood flow and exposure to systemic therapies, lacks established human models for assessing gene therapies. We utilized kidney organoids as a preclinical platform to test CRISPR/Cas9 genome editing via adeno-associated virus (AAV) delivery, a clinical strategy raising safety concerns due to toxic viral titers. We conduced RNA-seq to assess nephrotoxic responses.
2025-01-14 | GSE286037 | GEO
Project description: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.
2018-04-26 | GSE107230 | GEO
Project description:Nephron progenitor cells (NPCs) self-renew and differentiate into nephrons, the functional units of the kidney. Here we report manipulation of p38 and YAP activity creates a synthetic niche that allows the long-term clonal expansion of primary mouse and human NPCs, and induced NPCs (iNPCs) from human pluripotent stem cells. Cultured iNPCs resemble closely primary human NPCs, generating nephron organoids with abundant distal convoluted tubule cells, which are not observed in published kidney organoids. The synthetic niche reprograms differentiated nephron cells into NPC state, recapitulating the plasticity of developing nephron in vivo. Scalability and ease of genome-editing in the cultured NPCs allow for genome-wide CRISPR screening, identi-fying novel genes associated with kidney development and disease. A rapid, efficient, and scala-ble organoid model for polycystic kidney disease was derived directly from genome-edited NPCs, and validated in drug screen. These technological platforms have broad applications to kidney development, disease, plasticity, and regeneration.
2024-03-14 | GSE251862 | GEO
Project description:We report the first use of genome-edited human kidney organoids, combined with single-cell transcriptomics, to study APOL1 risk variants at the native genomic locus in different nephron cell types. This approach captures interferon-mediated induction of APOL1 gene expression and cellular dedifferentiation with a secondary insult“second hit” of endoplasmic reticulum stress.
2020-01-24 | GSE135663 | GEO
Project description:Safety issues of human iPSC-derived kidney organoids as a regenerative therapy need to be evaluated. Therefore, we studied the immunogenicity of human iPSC-derived kidney organoids. We subcutaneously implanted kidney organoids in immune-deficient IL2Ry-/-RAG2-/- mice for 1 month and hereafter performed adoptive transfer of healthy allogeneic human PBMC. We used single cell RNA sequencing (scRNA-seq) to analyze the diversity of kidney organoid cells and immune cell profiles. We investigated whether innate and adaptive immune cells invade kidney organoids, evoke an immune response, and influence the kidney organoid differentiation and functional capacity. Understanding the immunogenicity of kidney organoids will advance studies in the applicability of kidney organoids for regenerative medicine. Furthermore, it can serve as an in-vivo transplantation model to study solid organ transplantation.
2022-08-25 | GSE211803 | GEO
Project description:Single-Cell Transcriptomics of Genome-Edited Kidney Organoids
| PRJNA559570 | ENA
Project description:Kidney organoids were generated from a control iPSC line using a previously published protocol (https://doi.org/10.1038/nprot.2016.098). Organoids were collected at three timepoints during the protocol (day 14, 18 and 25) and prepared for proteomic analyses. The focus of the study was to define the proteomic composition of kidney organoids during differentiation with a particular emphasis on the extracellular matrix and its comparison to in vivo systems. Following a ample fractionation and matrix enrichment strategy, samples were prepared for high resolution label-free tandem mass spectrometry to define the proteomic composition of human kidney organoids.
2021-10-13 | PXD025838 | Pride
Project description:Hepatocyte nuclear factor 1B (HNF1B) encodes a transcription factor expressed in developing human kidney epithelia. Heterozygous HNF1B mutations are the commonest monogenic cause of dysplastic kidney malformations (DKMs). To understand their pathobiology, we generated heterozygous HNF1B mutant kidney organoids from CRISPR-Cas9 gene-edited human ESCs and iPSCs reprogrammed from a family with HNF1B-asscociated DKMs. Mutant organoids contained enlarged malformed tubules and displayed deregulated cell turnover. This submission is RNAseq of organoids from MAN13 embryonic stem cells.
2024-04-29 | E-MTAB-12824 | biostudies-arrayexpress
Project description:Transcriptome analysis of kidney organoids
| PRJNA421416 | ENA