Kidney-gut-brain cross talk in longterm IRI
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB73330 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR12710586_1.fastq.gz | Fastqsanger.gz | |||
| ERR12710586_2.fastq.gz | Fastqsanger.gz | |||
| ERR12710587_1.fastq.gz | Fastqsanger.gz | |||
| ERR12710587_2.fastq.gz | Fastqsanger.gz | |||
| ERR12710588_1.fastq.gz | Fastqsanger.gz |
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Project description:Integration of spatial and single cell transcriptomics localizes epithelial-immune cross-talk in kidney injury
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Project description:Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized as progressive and irreversible fibrosis in the interstitium of lung tissues. There is still an unmet need to develop a novel therapeutic drug for IPF. We have previously demonstrated that periostin, a matricellular protein, plays an important role in the pathogenesis of pulmonary fibrosis. However, the underlying mechanism of how periostin causes pulmonary fibrosis remains unclear. In this study, we sought to see whether the cross-talk between transforming growth factor-b (TGF-b), a central mediator in the pathogenesis of pulmonary fibrosis, and periostin in lung fibroblasts leads to generation of pulmonary fibrosis and whether taking advantage of the cross-talk between TGF-b and periostin, inhibitors for integrin aVb3, a periostin receptor, can block pulmonary fibrosis in the model mice. We found that there exists a cross-talk between TGF-b and periostin signals via aVb3/b5 converging into Smad3. This cross-talk is important for expression of several downstream molecules of TGF-b including serpin family E member 1, CCN family member 2/connective tissue growth factor, insulin-like growth factor binding protein-3, and IL-11, all of which have been already shown to be important for pulmonary fibrosis. We, moreover, found several potent integrin inhibitors to block the cross-talking with TGF-b signals and CP4715, one of the compounds, improved bleomycin-induced pulmonary fibrosis in mice. These results suggest that the cross-talk between TGF-b and periostin can be targeted for pulmonary fibrosis and that CP4715 can be a potential therapeutic agent to block the cross-talk between TGF-b and periostin.
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Project description:Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized as progressive and irreversible fibrosis in the interstitium of lung tissues. There is still an unmet need to develop a novel therapeutic drug for IPF. We have previously demonstrated that periostin, a matricellular protein, plays an important role in the pathogenesis of pulmonary fibrosis. However, the underlying mechanism of how periostin causes pulmonary fibrosis remains unclear. In this study, we sought to see whether the cross-talk between transforming growth factor-b (TGF-b), a central mediator in the pathogenesis of pulmonary fibrosis, and periostin in lung fibroblasts leads to generation of pulmonary fibrosis and whether taking advantage of the cross-talk between TGF-b and periostin, inhibitors for integrin aVb3, a periostin receptor, can block pulmonary fibrosis in the model mice. We found that there exists a cross-talk between TGF-b and periostin signals via aVb3/b5 converging into Smad3. This cross-talk is important for expression of several downstream molecules of TGF-b including serpin family E member 1, CCN family member 2/connective tissue growth factor, insulin-like growth factor binding protein-3, and IL-11, all of which have been already shown to be important for pulmonary fibrosis. We, moreover, found several potent integrin inhibitors to block the cross-talking with TGF-b signals and CP4715, one of the compounds, improved bleomycin-induced pulmonary fibrosis in mice. These results suggest that the cross-talk between TGF-b and periostin can be targeted for pulmonary fibrosis and that CP4715 can be a potential therapeutic agent to block the cross-talk between TGF-b and periostin.
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Project description:Cancer associated fibroblasts (CAFs), mainly responsible for the desmoplastic reaction hallmark of intrahepatic Cholangiocarcinoma (iCCA), likely take a role in tumour aggressiveness and resistance to therapy, although the molecular mechanisms involved are unknown. Aim of the study is to investigate how targeting hCAF/iCCA cross-talk with a Notch1 inhibitor namely Crenigacestat would affect cancer progressionWe used different in vitro models in 2D and we established new 3D hetero-spheroids with iCCA cells and human (h)CAFs. Results were confirmed in a xenograft model, explanted tumoral tissues underwent transcriptomic and bioinformatic analysis. hCAFs/iCCA cross-talk sustains increased migration of both KKU-M213 and KKU-M156 cells, while Crenigacestat significantly inhibits only the cross-talk stimulated migration. Hetero-spheroids grow larger than homo-spheroids,formed by only iCCA cells. Crenigacestat significantly reduced invasion and growth of hetero- but not of homo-spheroids. In xenograft models, hCAFs/KKU-M213 tumours grew significantly larger than KKU-M213 tumours, but were significantly reduced in volume by Crenigacestat treatment, which also significantly reduced the fibrotic reaction. Interpretative phenomenological analysis of the transcriptome unveiled that genes of hCAFs/KKU-M213 but not of KKU-M213 tumours increased tumour lesions, and that Crenigacestat treatment inhibited the modulated canonical pathway. Cell cycle checkpoints were the most modulated pathway. In hetero-spheroids, the number of cells increased into G2/M cell cycle phase, while Crenigacestat significantly decreased the number into G2/M phase in hetero but not in homo-spheroids. The cross-talk hCAFs/iCCA is a new target for reducing cancer progression with drugs such as Crenigacestat.
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Project description:The aim of this study was to identify miRNAs that regulate AKI and develop their applications as diagnostic biomarkers and therapeutic agents. First, kidney tissues from two different AKI mouse models, namely, AKI induced by the administration of lipopolysaccharide (LPS) causing sepsis (LPS-AKI mice) and AKI induced by renal ischemia–reperfusion injury (IRI-AKI mice), were exhaustively screened for their changes of miRNA expression compared with that of control mice by microarray analysis.
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2021-07-21 | GSE161201 | GEO
Project description:Single cell sequencing studies have characterized the transcriptomic signature of cell types within the kidney. However, the spatial distribution of acute kidney injury (AKI) is regional and affects cells heterogeneously. We first optimized coordination of spatial transcriptomics and single nuclear sequencing datasets, mapping 30 dominant cell types to a human nephrectomy. The predicted cell type spots corresponded with the underlying histopathology. To study the implications of AKI on transcript expression, we then characterized the spatial transcriptomic signature of two murine AKI models: ischemia reperfusion injury (IRI) and cecal ligation puncture (CLP). Localized regions of reduced overall expression were associated with injury pathways. Using single cell sequencing, we deconvoluted the signature of each spatial transcriptomic spot, identifying patterns of colocalization between immune and epithelial cells. Neutrophils infiltrated the renal medulla in the ischemia model. Atf3 was identified as a chemotactic factor in S3 proximal tubules. In the CLP model, infiltrating macrophages dominated the outer cortical signature and Mdk was identified as a corresponding chemotactic factor. The regional distribution of these immune cells was validated with multiplexed CO-Detection by inDEXing (CODEX) immunofluorescence. Spatial transcriptomic sequencing complements single cell sequencing by uncovering mechanisms driving immune cell infiltration and detection of relevant cell subpopulations.
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Project description:Incomplete repair after acute kidney injury (AKI) is associated with progressive loss of tubular cell function and development of chronic kidney disease (CKD). Here, we compared the kidney single-cell transcriptomes from the mice subjected to either unilateral ischemia-reperfusion kidney injury with contralateral nephrectomy (IRI/CL-NX, in which tubule repair predominates) or unilateral IRI with contralateral kidney intact (U-IRI, in which fibrosis and atrophy predominates) to investigate the mechanism(s) underlying transition to CKD following AKI.
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