Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1153012 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30420682_1.fastq.gz | Fastqsanger.gz | |||
| SRR30420682_2.fastq.gz | Fastqsanger.gz |
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Project description:This study reports the cellular self-organization of primary human renal proximal tubule epithelial cells (RPTECs) around a minimal Matrigel scaffold to produce basal-in and apical-out proximal tubule organoids (tubuloids). These tubuloids are produced and maintained in hanging drop cultures for 90+ days, the longest such culture of any kind reported to date. The tubuloids upregulate maturity markers, such as aquaporin-1 (AQP1) and megalin (LRP2), and exhibit less mesenchymal and proliferation markers, such as vimentin and Ki67, compared to 2D cultures. They also experience changes over time as revealed by a comparison of gene expression patterns of cells in 2D culture and in day 31 and day 67 tubuloids. Gene expression analysis and immunohistochemistry reveal an increase in the expression of megalin, an endocytic receptor that can directly bind and uptake protein or potentially assist protein uptake. The tubuloids, including day 90 tubuloids, uptake fluorescent albumin and reveal punctate fluorescent patterns, suggesting functional endocytic uptake through these receptors. Furthermore, the tubuloids release kidney injury molecule-1 (KIM-1), a common biomarker for kidney injury, when exposed to albumin in both dose- and time-dependent manners. While this study focuses on potential applications for modeling proteinuric kidney disease, the tubuloids may have broad utility for studies where apical proximal tubule cell access is required.
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Project description:Adult Stem Cell (ASC )-derived organoids are 3D epithelial structures that recapitulate essential aspects of their organ of origin. We have developed conditions for the long-term growth of primary kidney tubular epithelial organoids (‘tubuloids’). Cultures can be established from mouse and human kidney tissue, as well as from urine and can be expanded for at least 20 passages (> 6 months). The structures retain a normal number of chromosomes. Human tubuloids represent proximal as well as distal nephron segments, as evidenced by gene expression, immunofluorescence and tubular functional analyses. BK virus infection of tubuloids recapitulates in vivo phenomena. "Tumoroids" can be established from Wilms nephroblastoma. Kidney tubuloids from urine from a subject with Cystic Fibrosis (CF) allows ex vivo assessment of treatment efficacy. Finally, tubuloids cultured on microfluidic organ-on-a-chip plates adopt a tubular conformation and display active (trans-)epithelial transport function. Adult kidney-derived epithelial tubuloids allow studies of hereditary, infectious and malignant kidney disease in a personalized fashion.
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Project description:Adult Stem Cell (ASC )-derived organoids are 3D epithelial structures that recapitulate essential aspects of their organ of origin. We have developed conditions for the long-term growth of primary kidney tubular epithelial organoids (‘tubuloids’). Cultures can be established from mouse and human kidney tissue, as well as from urine and can be expanded for at least 20 passages (> 6 months). The structures retain a normal number of chromosomes. Human tubuloids represent proximal as well as distal nephron segments, as evidenced by gene expression, immunofluorescence and tubular functional analyses. BK virus infection of tubuloids recapitulates in vivo phenomena. "Tumoroids" can be established from Wilms nephroblastoma. Kidney tubuloids from urine from a subject with Cystic Fibrosis (CF) allows ex vivo assessment of treatment efficacy. Finally, tubuloids cultured on microfluidic organ-on-a-chip plates adopt a tubular conformation and display active (trans-)epithelial transport function. Adult kidney-derived epithelial tubuloids allow studies of hereditary, infectious and malignant kidney disease in a personalized fashion.
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Project description:Kidney organoids can be generated from commercially available human induced pluripotent stem cells (iPSC). They are amenable for genetic manipulation and useful for modelling development and early-onset genetic diseases. However, iPSC-derived kidney organoids lack longevity to model chronic stressors associated with chronic kidney disease. Adult epithelial kidney organoids (tubuloids) derived from nephrectomies or from renal cells suspended in urine can be passaged, expanded and cryopreserved, offering avenues to model epithelial injury and repair over longer timeframes. However, patient-derived organoids face regulatory barriers in their utilization. To leverage the benefits of both models, we establish a new protocol to generate tubuloids from iPSC-derived kidney organoids (iTubuloids). Kidney organoids were produced from iPSCs by directed differentiation then dissociated and cultured under adult organoid culture conditions. Epithelial organoids formed in less than 3 days from three distinct iPSC lines, each of which have been passaged > 12 times. Comparative analysis of gene expression profiles with RNA sequencing suggested that adult-derived tubuloids better represented the collecting duct, and iTubuloids showed increased expression of proximal and some distal markers. However, expression of proximal tubule markers was higher in iPSC-derived kidney organoids than any tubuloid model. We then evaluated the capacity of iTubuloids to model repetitive kidney injury and found exacerbation of the response and signs of failed repair as the injured progressed. Our study affirms capacity to extend the lifespan of epithelial cell types from short-lived iPSC-derived kidney organoids and reveal a need to optimise nephron cell identities in the tubuloid culture.
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