A comprehensive immune cell atlas of cystic kidney disease reveals the involvement of adaptive immune cells in injury mediated cyst progression
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ABSTRACT:
PROVIDER: PRJNA796540 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17584900.fastq.gz | Fastqsanger.gz | |||
| SRR17584901.fastq.gz | Fastqsanger.gz | |||
| SRR17584902.fastq.gz | Fastqsanger.gz | |||
| SRR17584903.fastq.gz | Fastqsanger.gz | |||
| SRR17584904.fastq.gz | Fastqsanger.gz |
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Project description:It is widely accepted that injuries to cilia mutant mice accelerate the rate of cystic kidney disease; however, cellular factors that drive the accelerated rate of cystic disease are unknown. By performing single cell RNA sequencing of all CD45+ immune cells, we find that the subtype and gene expression of adaptive immune cells is significantly altered between non-injured, aged cystic mice, injury-accelerated cystic mice, and non-cystic controls. Deletion of all adaptive immune cells reduced cystic disease in the injury-accelerated model but had no effect on cystic disease in the non-injured model. This differential rescue may be due to unique adaptive immune cell subtypes and ligands that are only present in the injury accelerated model of cystic disease.
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Project description:BackgroundInducible disruption of cilia-related genes in adult mice results in slowly progressive cystic disease, which can be greatly accelerated by renal injury.MethodsTo identify in an unbiased manner modifier cells that may be influencing the differential rate of cyst growth in injured versus non-injured cilia mutant kidneys at a time of similar cyst severity, we generated a single-cell atlas of cystic kidney disease. We conducted RNA-seq on 79,355 cells from control mice and adult-induced conditional Ift88 mice (hereafter referred to as cilia mutant mice) that were harvested approximately 7 months post-induction or 8 weeks post 30-minute unilateral ischemia reperfusion injury.ResultsAnalyses of single-cell RNA-seq data of CD45+ immune cells revealed that adaptive immune cells differed more in cluster composition, cell proportion, and gene expression than cells of myeloid origin when comparing cystic models with one another and with non-cystic controls. Surprisingly, genetic deletion of adaptive immune cells significantly reduced injury-accelerated cystic disease but had no effect on cyst growth in non-injured cilia mutant mice, independent of the rate of cyst growth or underlying genetic mutation. Using NicheNet, we identified a list of candidate cell types and ligands that were enriched in injured cilia mutant mice compared with aged cilia mutant mice and non-cystic controls that may be responsible for the observed dependence on adaptive immune cells during injury-accelerated cystic disease.ConclusionsCollectively, these data highlight the diversity of immune cell involvement in cystic kidney disease.
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Project description:Initial cysts that are formed upon Pkd1 loss in mice impose persistent stress on surrounding tissue and trigger a cystic snowball effect, in which local aberrant PKD-related signaling increases the likelihood of new cyst formation, ultimately leading to accelerated disease progression. Although many pathways have been associated with PKD progression, the knowledge of early changes near initial cysts is limited. To perform an unbiased analysis of transcriptomic alterations in the cyst microenvironment, microdomains were collected from kidney sections of iKsp-Pkd1del mice with scattered Pkd1-deletion using Laser Capture Microdissection. These microdomains were defined as F4/80-low cystic, representing early alterations in the cyst microenvironment, F4/80-high cystic, with more advanced alterations, or non-cystic. RNA sequencing and differential gene expression analysis revealed 953 and 8088 dysregulated genes in the F4/80-low and F4/80-high cyst microenvironment, respectively, when compared to non-cystic microdomains. In the early cyst microenvironment, several injury-repair, growth, and tissue remodeling-related pathways were activated, accompanied by mild metabolic changes. In the more advanced F4/80-high microdomains, these pathways were potentiated and the metabolism was highly dysregulated. Upstream regulator analysis revealed a series of paracrine factors with increased activity in the early cyst microenvironment, including TNFSF12 and OSM. In line with the upstream regulator analysis, TWEAK and Oncostatin-M promoted cell proliferation and inflammatory gene expression in renal epithelial cells and fibroblasts in vitro. Collectively, our data provide an overview of molecular alterations that specifically occur in the cyst microenvironment and identify paracrine factors that may mediate early and advanced alterations in the cyst microenvironment.
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Project description:We show that resident macrophages accumulate in cilia mutant mice prior to cyst formation and that inhibition of resident macrophage accumulation reduces cystic kidney disease.
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Project description:Intraductal papillary mucinous neoplasm (IPMN) is a duct-dilating precancerous lesion that grows in pancreatic ducts and is accompanied by the production of mucinous fluid. In recent years, its cystic fluid has been used molecularly for the differential diagnosis of other cystic tumors and malignancies. Thus, proteomic research of IPMN cyst fluid must be performed to identify an effective diagnostic biomarker. We examined the IPMN cyst fluid proteome using a novel proteomic strategy, combined with high-resolution LC-MS/MS. Although we did not deplete any high-abundance proteins, our dataset consistently detected thousands of proteins including pancreatic tumor markers, such as mucin family members, S100 proteins, and CEA-related proteins. In addition, we found 590 protein mutations through a variant sequence database search. Bioinformatics analyses were performed to determine biological functions and clinical meanings of canonical IPMN proteins and mutated proteins. Our proteomic platform and in-depth proteome dataset are valuable references that can be used in future studies.
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Project description:OBJECTIVE: Due to the common occurrence of peritumoral cysts throughout the central nervous system tumors, hemangioblastomas (HBs) provide a model of cyst to further study the molecular mechanisms of peritumoral cyst formation. METHODS: We conducted an integrated lipidomics and transcriptomics analysis on solid and cyst HB samples, to elucidate the changes in lipid profile and the expression levels of genes associated with lipid metabolism in the cyst formation. RESULTS: Transcriptomic analysis revealed differentially expressed genes between the solid and cystic HBs. The lipidomic analysis further showed a significant reduction in the abundance of triacylglycerol, ceramide, lysophosphatidylcholine, and lysophosphatidylethanolamine, and an increase in phosphatidylcholine and phosphatidylethanolamine in the cystic group. Besides, bioinformatics analysis revealed altered lipid biosynthesis, glycerophospholipid metabolism and phospholipase activity in the cyst HBs. CONCLUSION: Our findings indicate that aberrant lipid metabolism is a causative factor of cyst formation in HBs, and provide novel insights into the role of lipid metabolism in HBs.
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Project description:Determination of pancreatic cyst fluids (PCF) peptidome and proteome in 5 distinct patient groups: malignant (CAs), intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), serous cystic neoplasms (SCNs), and pseudocysts (PCs). The PCF <5kDa fraction, referred as the degradome, and proteome profiles were determined using a LTQ-Orbitrap Elite mass spectrometer coupled with a nanoAcquity LC system. Qualitative LC-MS/MS analyses were ran on pooled samples from all patients.
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Project description:The increased number of pancreatic cyst lesions (PCLs) have been detected through the development of abdominal imaging techniques, such as computed tomography (CT), magnetic resonance imaging (MRI), and endoscopic ultrasound (EUS). However, accurate classification of cystic lesions is difficult because of the lack of standardized diagnostic methods, and thus potentially unnecessary surgical resection has been performed on pancreatic cyst patients. Among four most common types of cystic lesions of pancreas, intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCN), serous cystic neoplasms (SCN), and solid pseudopapillary neoplasms (SPNs), IPMNs, the precursor lesion of pancreatic cancer, have been detected most frequently, and are subdivided into low-grade dysplasia (LGD), high-grade dysplasia (HGD), and invasive IPMN in accordance with their malignancy. To discover the potential biomarkers of the histological grades of IPMN, we investigated pancreatic cyst fluid proteins that are differentially expressed in accordance with the IPMN malignancy by LC-MS/MS analysis.
2020-09-06 | PXD016127 | Pride
Project description:Polycystic Kidney Disease is characterized by the formation of large fluid-filled cysts that eventually destroy the renal parenchyma leading to end-stage renal failure. Although remarkable progress has been made in understanding the pathologic mechanism of the disease, the precise orchestration of the early events leading to cyst formation is still unclear. Abnormal cellular proliferation was traditionally considered to be one of the primary irregularities leading to cyst initiation and growth. Consequently, many therapeutic interventions have focused on targeting this abnormal proliferation, and some have even progressed to clinical trials. However, the role of proliferation in cyst development was primarily examined at stages where cysts are already visible in the kidneys and therefore at later stages of disease development. In this study we focused on the cystic phenotype since birth in an attempt to clarify the temporal contribution of cellular proliferation in cyst development. Using a PKD2 transgenic rat model (PKD2 (1-703)) of different ages (0-60 days after birth) we performed gene expression profiling and phenotype analysis by measuring various kidney parameters. Phenotype analysis demonstrated that renal cysts appear immediately after birth in the PKD2 transgenic rat model (PKD2 (1-703)). On the other hand, abnormal proliferation occurs at later stages of the disease as identified by gene expression profiling. Interestingly, other pathways appear to be deregulated at early stages of the disease in this PKD model. Our data suggest that cystogenesis precedes deregulation of proliferation-related pathways, suggesting that proliferation abnormalities may contribute in cyst growth rather than cyst formation. In this study we focused on the cystic phenotype since birth in an attempt to clarify the temporal contribution of cellular proliferation in cyst development. Using a PKD2 transgenic rat model (PKD2 (1-703)) of different ages (0,6 and 24 days after birth) we performed gene expression profiling of kidney cells.
2010-01-31 | E-GEOD-19460 | biostudies-arrayexpress
Project description:Introduction: The mechanism by which adamantinomatous craniopharyngioma (ACP) damages the hypothalamus is still unclear. Cyst fuid rich in lipids and infammatory factors is a characteristic pathological manifestation of ACP and may play a very important role in hypothalamic injury caused by tumors. Objective: The objective of this study was to construct a reliable animal model of ACP cyst fuid-induced hypotha lamic injury and explore the specifc mechanism of hypothalamic injury caused by cyst fuid. Methods: An animal model was established by injecting human ACP cyst fuid into the bilateral hypothalamus of mice. ScRNA-seq was performed on the mice hypothalamus and on an ACP sample to obtain a complete gene expression profle for analysis. Data verifcation was performed through pathological means. Results: ACP cystic fuid caused growth retardation and an increased obesity index in mice, afected the expres sion of the Npy, Fgfr2, Rnpc3, Sst, and Pcsk1n genes that regulate growth and energy metabolism in hypothalamic neurons, and enhanced the cellular interaction of Agrp–Mc3r. ACP cystic fuid signifcantly caused infammatory activation of hypothalamic microglia. The cellular interaction of CD74–APP is signifcantly strengthened between infammatory activated microglia and hypothalamic neurons. Beta-amyloid, a marker of neurodegenerative diseases, was deposited in the ACP tumor tissues and in the hypothalamus of mice injected with ACP cyst fuid. Conclusion: In this study, a novel animal model of ACP cystic fuid-hypothalamic injury was established. For the frst time, it was found that ACP cystic fuid can trigger infammatory activation of microglia to damage the hypothalamus, which may be related to the upregulation of the CD74–APP interaction and deposition of β-amyloid, implying that there may be a similar mechanism between ACP cystic fuid damage to the hypothalamus and neurodegenerative diseases.
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