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Establishment of epithelial inflammatory injury model using adult kidney organoids [RNA-seq]

ABSTRACT: Kidney organoids are emerging as an increasingly applied model system to hold great promise for transplantation to individuals with end-stage renal disease and as a useful tool for kidney research. Multiple iPSC-derived renal organoids have been established to understand kidney development and disease. However, few disease models originated from adult renal tissue with fully mature cell fates have been set up to recapitulate kidney inflammation or fibrosis. Here we created a novel organoid model that faithfully representing the cellular state of inflammatory response during the progression of renal disease upon TNFα exposure. scRNA-seq showed signatured inflammatory chemokines, cytokines and inflammation-associated signaling pathways were activated in TNFα-treatment organoids together with injury-associated markers such as LCN2 and CLU. Donor age is associated with TNFα-induced inflammatory reaction in organoids. Kidney organoids from young donors showed more transcriptional changes by down-regulation of TGFβ and extracellular matrix genes. In summary, we established an in vitro TNFα-treated kidney organoid model that representing the cellular state of the inflammatory response during renal disease progression and provided a novel tool for studying inflammation-related kidney disease and drug discovery.

ORGANISM(S): Homo sapiens

PROVIDER: GSE259376 | GEO | 2024/03/03

REPOSITORIES: GEO

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Establishment of epithelial inflammatory injury model using adult kidney organoids [scRNA-seq]

Project description:Kidney organoids are emerging as an increasingly applied model system to hold great promise for transplantation to individuals with end-stage renal disease and as a useful tool for kidney research. Multiple iPSC-derived renal organoids have been established to understand kidney development and disease. However, few disease models originated from adult renal tissue with fully mature cell fates have been set up to recapitulate kidney inflammation or fibrosis. Here we created a novel organoid model that faithfully representing the cellular state of inflammatory response during the progression of renal disease upon TNFα exposure. scRNA-seq showed signatured inflammatory chemokines, cytokines and inflammation-associated signaling pathways were activated in TNFα-treatment organoids together with injury-associated markers such as LCN2 and CLU. Donor age is associated with TNFα-induced inflammatory reaction in organoids. Kidney organoids from young donors showed more transcriptional changes by down-regulation of TGFβ and extracellular matrix genes. In summary, we established an in vitro TNFα-treated kidney organoid model that representing the cellular state of the inflammatory response during renal disease progression and provided a novel tool for studying inflammation-related kidney disease and drug discovery.

2024-03-03 | GSE259381 | GEO

Kidney Organoids treated with TNFa at 5 ng/mL and 50ng/mL for 24h and 48h

Project description:This dataset serves as comparison for PXD029718 using a different organoid differentiation protocol – as requested by reviewers. Kidney organoids are a promising model to study kidney disease, but use is constrained by limited knowledge of their functional protein expression profile. We aimed to define the organoid proteome and transcriptome trajectories over culture duration and upon exposure to TNFα, a cytokine stressor. Older organoids increased deposition of extracellular matrix but decreased expression of glomerular proteins. Single cell transcriptome integration revealed that most proteome changes localized to podocytes, tubular and stromal cells. TNFα-treatment of organoids effected 320 differentially expressed proteins, including cytokines and complement components. Transcript expression of these 320 proteins was significantly higher in individuals with poorer clinical outcomes in proteinuric kidney disease. Key TNFα-associated protein (C3 and VCAM1) expression was increased in both human tubular and organoid kidney cell populations, highlighting the potential for organoids to advance biomarker development. By integrating kidney organoid omic layers, incorporating a disease-relevant cytokine stressor and comparing to human data, we provide crucial evidence of functional relevance of the kidney organoid model to human kidney disease.

2023-05-12 | PXD040812 | Pride

Kidney micro-organoids generated in suspension culture

Project description:Kidney organoids have potential uses in disease modelling, drug screening and regenerative medicine. However, novel cost-effective techniques are needed to enable scale-up production of kidney cell types in vitro. We describe here a modified suspension culture method for the generation of kidney micro-organoids from human pluripotent stem cells. Each micro-organoid contains 6-10 nephrons surrounded by endothelial and stromal populations. Single cell transcriptional profiling confirmed the presence and transcriptional equivalence of all anticipated renal cell types consistent with a previous organoid culture method. Ligand-receptor mapping identified TGFβ signalling between stromal and epithelial cell types as likely to result in fibrotic changes observed with long-term culture. The addition of an ALK4 inhibitor suppressed stromal expansion, maintaining epithelial morphology and improving maturation. This suspension culture micro-organoid methodology resulted in a 3-4-fold increase in final cell yield compared to static culture, thereby representing an economical approach to the production of kidney cells for various biological applications.

2019-03-01 | GSE117211 | GEO

Developing a novel human adult kidney organoid model to recapitulate injury-associated regeneration and polycystic kidney disease [RNA-Seq]

Project description:Current renal organoid models derived from embryonic or induced pluripotent stem cells mimic development. Yet, few studies have attempted to generate organoids from human adult kidney to recapitulate regeneration or pathological dysregulation in vitro. Here, we report a novel expanding regenerative organoids culture system from renal cortex and medulla. Transcriptomic sequencing and immunostaining identified that these organoids share similar molecular features with kidney injury-responsive regeneration. Heterogeneous populations in organoids including cycling epithelial progenitors and differentiated cell types were identified by single cell sequencing including proximal tubules, principal cells and collecting duct (CD) progenitors that can be induced into functional CD system. Furthermore, we established polycystic organoids derived from patients that represent an advanced platform for polycystic kidney disease (PKD) modeling. By drug screening, QNZ, GSK2193874 and AMPK activators were shown to significantly reduce polycystic growth. Our results demonstrated a novel in vitro renal organoid model to study regenerating adult renal cells and PKD mechanism, providing tools for discovery of therapeutic targets.

2023-08-28 | GSE228971 | GEO

Developing a novel human adult kidney organoid model to recapitulate injury-associated regeneration and polycystic kidney disease [scRNA-Seq]

2023-08-31 | GSE241972 | GEO

Response of HK-2 cells to stimulation with IL6 and TNF-alpha (90 minutes)

Project description:Abstract: Human kidney function declines with age, accompanied by stereotyped changes in gene expression and histopathology, but the mechanisms underlying these changes are largely unknown. We compared age-associated changes in global gene expression patterns in the human kidney with genome-wide maps of transcription factor occupancy in human cell lines to identify potential regulators of gene expression changes in the aging kidney. The strongest associations involved three inflammation-associated transcription factors: NFκB, STAT1 and STAT3. We found that the activity of these transcription factors increases with age in epithelial compartments of the renal cortex. Stimulation of renal tubular epithelial cells with the inflammatory cytokines IL-6 (a STAT3 activator), IFN-γ (a STAT1 activator), or TNFα (an NFκB activator) recapitulated age-associated gene expression changes. We found that common DNA variants in the two genes that encode the subunits of the canonical NFκB transcription factor (RELA and NFKB1) showed significant associations with kidney function and chronic kidney disease in gene association studies, providing the first evidence for a direct link between genetic variation in NFκB and individual differences in age-related phenotypes in the kidney. Our results point to chronic inflammation, mediated by NFκB, STAT1 and STAT3, as a dominant mechanism influencing gene expression changes during kidney aging. Biological triplicate experiments were performed for each cytokine treatment condition or control treatment.

2015-07-01 | E-GEOD-68940 | biostudies-arrayexpress

Response of HK-2 cells to stimulation with IL6 and TNF-alpha (72 hours)

2015-07-01 | E-GEOD-68941 | biostudies-arrayexpress

Response of HK-2 cells to stimulation with IFN, IL6 and TNF-alpha in different combinations

Project description:Abstract: Human kidney function declines with age, accompanied by stereotyped changes in gene expression and histopathology, but the mechanisms underlying these changes are largely unknown. We compared age-associated changes in global gene expression patterns in the human kidney with genome-wide maps of transcription factor occupancy in human cell lines to identify potential regulators of gene expression changes in the aging kidney. The strongest associations involved three inflammation-associated transcription factors: NFκB, STAT1 and STAT3. We found that the activity of these transcription factors increases with age in epithelial compartments of the renal cortex. Stimulation of renal tubular epithelial cells with the inflammatory cytokines IL-6 (a STAT3 activator), IFN-γ (a STAT1 activator), or TNFα (an NFκB activator) recapitulated age-associated gene expression changes. We found that common DNA variants in the two genes that encode the subunits of the canonical NFκB transcription factor (RELA and NFKB1) showed significant associations with kidney function and chronic kidney disease in gene association studies, providing the first evidence for a direct link between genetic variation in NFκB and individual differences in age-related phenotypes in the kidney. Our results point to chronic inflammation, mediated by NFκB, STAT1 and STAT3, as a dominant mechanism influencing gene expression changes during kidney aging. Biological duplicate or triplicate experiments were profiled for each cytokine treatment or control condition

2015-07-01 | E-GEOD-68942 | biostudies-arrayexpress

An Organoid Biobank for Childhood Kidney Cancers that Captures Disease and Tissue Heterogeneity

Project description:Kidney tumours are among the most common solid tumours in children, comprising several distinct subtypes differing in many aspects, including cell-of-origin, genetics, and pathology. Pre-clinical cell models capturing the disease heterogeneity are currently lacking. Here, we describe the first paediatric cancer organoid biobank. It contains tumour and matching normal kidney organoids from over 50 children with different subtypes of kidney cancer, including Wilms tumours, malignant rhabdoid tumours, renal cell carcinomas, and congenital mesoblastic nephromas. The malignant rhabdoid tumour organoids represent the first organoid model for tumours of non-epithelial origin. The tumour organoids retain key properties of native tumours, useful for revealing patient-specific drug vulnerabilities. We further demonstrate that organoid cultures derived from Wilms tumours consist of multiple different cell types, including epithelial, stromal and blastemal-like. Our organoid biobank captures the cellular heterogeneity of paediatric kidney tumours, providing a representative collection of well-characterized models for basic cancer research, drug-screening, and personalized medicine.

2019-09-18 | GSE137544 | GEO

iPSC-derived type IV collagen α5-expressing kidney organoids model Alport syndrome

Project description:Alport syndrome (AS) is a hereditary glomerulonephritis caused by COL4A3, COL4A4 or COL4A5 gene mutations and characterized by abnormalities of glomerular basement membranes (GBMs). Due to a lack of curative treatments, the condition proceeds to end-stage renal disease even in adolescents. Hampering drug discovery is the absence of effective in vitro methods for testing the restoration of normal GBMs. Here, we aimed to develop kidney organoid models from AS patient iPSCs for this purpose. We established iPSC-derived collagen α5(IV)-expressing kidney organoids and confirmed that kidney organoids from COL4A5 mutation-corrected iPSCs restore collagen α5(IV) protein expression. Importantly, our model recapitulates the differences in collagen composition between iPSC-derived kidney organoids from mild and severe AS cases. Furthermore, we demonstrate that a chemical chaperone, 4-phenyl butyric acid, has the potential to correct GBM abnormalities in kidney organoids showing mild AS phenotypes. This iPSC-derived kidney organoid model will contribute to drug discovery for AS.

2023-07-06 | GSE236314 | GEO

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