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Transcriptomic profiling of prolonged-culture iPSC-derived kidney organoids and X-linked Alport syndrome organoid models carrying COL4A5 deep-intronic variants

ABSTRACT: Transcriptomic profiling of prolonged-culture iPSC-derived kidney organoids and X-linked Alport syndrome organoid models carrying COL4A5 deep-intronic variants

PROVIDER: PRJNA1182234 | ENA |

REPOSITORIES: ENA

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Transcriptomic profiling of prolonged-culture iPSC-derived kidney organoids and X-linked Alport syndrome organoid models carrying COL4A5 deep-intronic variants

Project description:Kidney organoids serve as an invaluable platform for modeling hereditary renal diseases and developing therapeutic interventions. While various kidney organoid differentiation protocols have been developed, the protocol introduced by Morizane et al. was among the first to generate kidney organoids from induced pluripotent stem cells (iPSCs). By using a modified version of this protocol, we successfully generated kidney organoids in 21 days. Most studies on kidney organoids focus on early stages, typically between days 21 and 29, leaving the gene expression dynamics during prolonged culture less explored. In this study, we cultured healthy iPSC-derived kidney organoids for 22, 32, and 42 days and performed bulk RNA sequencing to investigate gene expression regulation during organoid culture. We also developed X-linked Alport syndrome (XLAS) organoid models carrying deep-intronic variants (severe and moderate models) to develop Antisense oligonucleotide (ASO) therapeutic approaches. Kidney organoids contain over 15 distinct cell types, making them a complex model for studying cell-type-specific maturation. By comparing organoids at early (day 22), mid (day 32), and late (day 42) time points, we observed significant changes in gene expression, particularly in genes related to the extracellular matrix, alongside the downregulation of podocyte-specific genes. Notably, we confirmed the upregulation of podocyte-specific collagen IV genes (COL4A3 and COL4A4), which are critical for forming the glomerular basement membrane (GBM). Overall, these findings underscore the importance of maintaining organoids in culture for at least 15 days beyond the last day of differentiation (day 21) to ensure the development of a more mature GBM, essential for BM disease modeling such as Alport syndrome.

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Single cell gene expression analysis of X-linked Alport syndrome kidney organoid models and isogenic controls

Project description:In study we investigated podocyte maturation, with a particular focus on type IV collagen maturation in the glomerular basement membrane (GBM) of kidney organoids over extended culture periods (comparing Control Organoid d22 R2 with Control Organoid d38). The secondary aim was to compare the gene expression profiles of podocytes in X-linked Alport syndrome (XLAS) organoid models with isogenic controls at an early culture time point (day 22). Two distinct batches of sample collection were conducted to capture early and later stages of GBM development. In the first batch, three libraries were generated by collecting 16 organoids from one isogenic control, one severe XLAS model, and one moderate XLAS model on day 22 of differentiation. In the second batch, two libraries were created to evaluate the impact of culture duration on GBM maturation by harvesting an additional isogenic control organoid at both day 22 and day 38 of culture. Organoids were dissociated using a two-step enzymatic and mechanical protocol to obtain single-cell suspensions, with cell viability ranging between 70% and 85%. This experimental design enabled a comparative analysis of GBM maturation dynamics between early and late time points and across different severities of XLAS. Findings from this study provided insights into the cellular mechanisms underlying GBM abnormalities in Alport syndrome and supported the potential for GBM maturation in kidney organoids over time.

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Spatial transcriptomics reveals key differences in Alport disease progression and potential targets of hEV treatment in Alport disease

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