Human iPSC-derived nephron progenitor cells treat AKI and CKD in mouse models
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ABSTRACT:
PROVIDER: PRJNA1228556 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32495214.fastq.gz | Fastqsanger.gz | |||
| SRR32495215.fastq.gz | Fastqsanger.gz | |||
| SRR32495216.fastq.gz | Fastqsanger.gz | |||
| SRR32495217.fastq.gz | Fastqsanger.gz | |||
| SRR32495218.fastq.gz | Fastqsanger.gz |
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Project description:The number of patients requiring dialysis therapy continues to increase worldwide due to the lack of effective treatments for chronic kidney disease (CKD). Furthermore, no curative treatments for acute kidney injury (AKI) have been established. The therapeutic effects of human induced pluripotent stem cell-derived nephron progenitor cells (hiPSC-NPCs) on AKI have been reported in mice but not clinically confirmed. There are also no reports examining the therapeutic potential of hiPSC-NPCs on CKD. Although large numbers of uniform hiPSC-NPCs are required for cell therapies for AKI and CKD, effective expansion cultures remain to be developed. Here, we established a CFY (CHIR99021, FGF9, Y-27632) medium for cell culture that enables more than 100-fold proliferation of hiPSC-NPCs from multiple hiPSC lines in two passages. We demonstrated that hiPSC-NPCs expanded by CFY or their conditioned medium alone attenuate kidney injury and improve survival in cisplatin-induced AKI mice. We also observed that hiPSC-NPCs prevented kidney functional decline, interstitial fibrosis, and senescence in aristolochic acid-induced CKD mice. In addition, we discovered c-MET as a specific cell surface marker for hiPSC-NPCs and confirmed that purified c-MET+ hiPSC-NPCs have therapeutic effects on AKI and CKD. Furthermore, we found that hiPSC-NPCs exerted their therapeutic effects in AKI and CKD mice by secreting vascular endothelial growth factor A (VEGF-A). Together, expanded hiPSC-NPCs are useful cell therapies for AKI and CKD, and may open new avenues for treating kidney diseases.
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Project description:Interstitial renal inflammation contributes to the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). Recently, protein lactylation modification has emerged as a novel mechanism mediating chronic organ damage. We investigated lactylated protein profiles and the role of protein lactylation during AKI progression. Severe and moderate AKI mouse models were constructed by bilateral renal ischemia for 35 and 25 min respectively. The lactylation enhancer and inhibitors were used to verify the effect of protein lactylation. Lactylated proteomics was used to detect lactylated protein changes in kidneys, and the lactylated proteins related to kidney injury were screened for verification. We observed significantly higher lactate and protein lactylation levels in the severe than in the moderate AKI model 1–28 days post-injury. Inhibition of protein lactylation protected against renal interstitial fibrosis. In vitro and in vivo experiments demonstrated that protein lactylation activated Nod-like receptor protein 3 (NLRP3) inflammasomes, promoting the AKI–CKD transition. Comprehensive lactylome profiling of severe AKI models revealed a role for lactylated proteins in metabolic pathways, primarily the tricarboxylic acid (TCA) cycle where the rate-limiting enzyme, citrate synthase (CS), exhibited significantly elevated lactylation levels 3–7 days post-AKI induction; K370 was the most significant lysine residue. In vitro, following hypoxia/reoxygenation, the modified/lactylated K370T group significantly decreased CS activity and mitochondrial function. Furthermore, CS-K370 lactylation activated the NLRP3 inflammasome. Lactylation of CS promotes the AKI–CKD transition through NLRP3 inflammasome activation. Inhibition of CS lactylation shows therapeutic potential for preventing this transition.
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Project description:Macrophages are key immune cells in AKI and may determine the fate of AKI to CKD progression. Here, by taking advantages of single cell RNA-sequencing technology, we generated a mononuclear macrophage atlas from the initiation of AKI till the progression to CKD.
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Project description:Studies in animal models have suggested a linkage between the inflammatory response to injury and subsequent nephron loss during the acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Failure of normal repair during the CKD transition correlates with de novo expression of vascular cell adhesion protein-1 (VCAM-1) by a subset of injured proximal tubule cells. This study identified the role of VCAM-1 expression in promoting the failed repair state. Single-cell transcriptome analysis of patients with AKI and CKD and whole kidney RNA and protein analyses of mouse models of CKD confirmed a marked increase of VCAM-1 expression in the proximal tubules of injured kidneys. In immortalized mouse proximal tubular cells and primary cultured renal cells (PCRCs), VCAM-1 expression was induced by proinflammatory cytokines including tumor necrosis factor (TNF)-α and interleukin (IL)-1β. Analyses of bulk RNA sequencing of TNF-α-treated primary cultured renal cells or pseudo-bulk RNA sequencing of biopsies from Kidney Precision Medicine Project datasets indicated activation of NF-κB and an enrichment of inflammatory response and cell adhesion pathways in VCAM-1-positive cells. Pharmacological inhibition of NF-κB signaling or genetic deletion of myeloid differentiation factor 88 and TIR domain-containing adapter-inducing interferon-β suppressed TNF-α- and IL-1β-induced VCAM-1 expression in vitro. TNF-α stimulation or overexpression of VCAM-1 significantly increased splenocyte adhesion to the mouse proximal tubular monolayer in culture. These results demonstrate that persistence of proinflammatory cytokines after AKI can induce NF-κB-dependent VCAM-1 expression by proximal tubule cells, mediating increased immune cell adhesion to the tubule and thus promoting further tubule injury and greater risk of progression from AKI to CKD.
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Project description:Acute kidney injury (AKI) is characterized by a rapid decline in renal function. In severe or recurrent cases, AKI can progress to chronic kidney disease (CKD), marked by renal inflammation and fibrosis. Despite the severity of these outcomes, early-stage diagnostic tools and pharmacological interventions for AKI-to-CKD progression remain limited. In this study, we examined circular RNA (circRNA) expression profiles in mouse renal cortex tissues 14 days post-ischemia/reperfusion (I/R) injury using circRNA sequencing. The renal biopsy samples of patients from AKI patients exhibited reduced CircNSD1 expression, which was inversely associated with inflammation and fibrosis. Overexpression of CircNSD1 attenuated ferroptosis in vivo and in vitro, thereby slowing AKI-to-CKD progression. Mechanistically, CircNSD1 downregulated ACSL4 and SlC39A14 expression through histone H3 lysine 36 (H3K36) methylation, a critical pathway regulating ferroptosis during AKI or hypoxia/reoxygenation (H/R) injury. Furthermore, we identified that CircNSD1 encoded a NSD1-916aa peptide, which may functionally contribute to its observed effect. Collectively, these findings demonstrated that CircNSD1 may serve as a diagnostic and therapeutic target for early detection of AKI-to-CKD transition.
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Project description:Low nephron numbers are associated with increased risk of developing chronic kidney disease (CKD) and hypertension, both significant global health problems. To investigate the impact of nephron deficiency, our lab developed a novel inbred rat model (HSRA rat). In this model, approximately 75% of offspring are born with a single kidney (HSRA-S), compared to two-kidney littermates (HSRA-C). HSRA-S rats show impaired kidney development, resulting in ~20% fewer nephrons. Our previous data and current findings demonstrate nephron deficit (failure of one kidney to form and altered development in the remaining kidney) predispose HSRA-S to CKD late in life (increased proteinuria by 18 months of age in HSRA-S=51± 3.4 versus HSRA-C = 8± 1.5 mg/24hours). To understand early molecular mechanisms contributing to the increased predisposition to CKD, Methylseq using reduced representation bisulfite sequencing, single nuclei (sn)RNAseq, and discovery proteomics were performed in kidneys of 4-week-old HSRA rats. Methylation analysis revealed a small number of differences, including 5 differentially methylated cytosines and 6 differentially methylated regions between groups. The snRNAseq analysis identified differentially expressed genes in most kidney cell types, with several hundred genes dysregulated depending on the analysis method (Seurat vs DESeq2). Notably, many genes are involved in kidney development. Discovery proteomic analysis identified 366 differentially expressed proteins. A key finding was dysregulation of Deptor/DEPTOR and Amdhd2/AMDHD2 across omics layers, suggesting a potential role in compensatory mechanisms or the genetic basis of altered kidney development. Further understanding of these mechanisms may guide interventions to preserve nephron health and slow kidney disease progression.
2025-07-09 | GSE289104 | GEO
Project description:Low nephron numbers are associated with increased risk of developing chronic kidney disease (CKD) and hypertension, both significant global health problems. To investigate the impact of nephron deficiency, our lab developed a novel inbred rat model (HSRA rat). In this model, approximately 75% of offspring are born with a single kidney (HSRA-S), compared to two-kidney littermates (HSRA-C). HSRA-S rats show impaired kidney development, resulting in ~20% fewer nephrons. Our previous data and current findings demonstrate nephron deficit (failure of one kidney to form and altered development in the remaining kidney) predispose HSRA-S to CKD late in life (increased proteinuria by 18 months of age in HSRA-S=51± 3.4 versus HSRA-C = 8± 1.5 mg/24hours). To understand early molecular mechanisms contributing to the increased predisposition to CKD, Methylseq using reduced representation bisulfite sequencing, single nuclei (sn)RNAseq, and discovery proteomics were performed in kidneys of 4-week-old HSRA rats. Methylation analysis revealed a small number of differences, including 5 differentially methylated cytosines and 6 differentially methylated regions between groups. The snRNAseq analysis identified differentially expressed genes in most kidney cell types, with several hundred genes dysregulated depending on the analysis method (Seurat vs DESeq2). Notably, many genes are involved in kidney development. Discovery proteomic analysis identified 366 differentially expressed proteins. A key finding was dysregulation of Deptor/DEPTOR and Amdhd2/AMDHD2 across omics layers, suggesting a potential role in compensatory mechanisms or the genetic basis of altered kidney development. Further understanding of these mechanisms may guide interventions to preserve nephron health and slow kidney disease progression.
2025-07-09 | GSE289103 | GEO