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RNA-sequencing of brain microvascular endothelial cell dysfunction in an isogenic juvenile iPSC model of Huntington’s disease

ABSTRACT: RNA-sequencing of brain microvascular endothelial cell dysfunction in an isogenic juvenile iPSC model of Huntington’s disease

PROVIDER: PRJNA800452 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17745603_1.fastq.gz	Fastqsanger.gz
	SRR17745603_2.fastq.gz	Fastqsanger.gz
	SRR17745604_1.fastq.gz	Fastqsanger.gz
	SRR17745604_2.fastq.gz	Fastqsanger.gz
	SRR17745605_1.fastq.gz	Fastqsanger.gz

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RNA-sequencing of brain microvascular endothelial cell dysfunction in an isogenic juvenile iPSC model of Huntington’s disease

Project description:Huntington's disease (HD) is associated with dysfunction of the blood-brain barrier, including brain microvasscular endothelial cells (BMECs). We report changes in gene expression of induced pluripotent stem cells (iPSCs) and iPSC-derived brain microvascular endothelial cell-like cells (iBMECs) derived from an isogenic pair of iPSCs with either 180 (HD-corrected) or 18 (HD180) CAG repeats in the HTT gene.

2022-02-01 | GSE194416 | GEO

Brain microvascular endothelial cell dysfunction in an isogenic juvenile iPSC model of Huntington's disease.

Project description:Huntington's disease (HD) is an inherited neurodegenerative disease caused by expansion of cytosine-adenine-guanine (CAG) repeats in the huntingtin gene, which leads to neuronal loss and decline in cognitive and motor function. Increasing evidence suggests that blood-brain barrier (BBB) dysfunction may contribute to progression of the disease. Studies in animal models, in vitro models, and post-mortem tissue find that disease progression is associated with increased microvascular density, altered cerebral blood flow, and loss of paracellular and transcellular barrier function. Here, we report on changes in BBB phenotype due to expansion of CAG repeats using an isogenic pair of induced pluripotent stem cells (iPSCs) differentiated into brain microvascular endothelial-like cells (iBMECs). We show that CAG expansion associated with juvenile HD alters the trajectory of iBMEC differentiation, producing cells with ~ two-fold lower percentage of adherent endothelial cells. CAG expansion is associated with diminished transendothelial electrical resistance and reduced tight junction protein expression, but no significant changes in paracellular permeability. While mutant huntingtin protein (mHTT) aggregates were not observed in HD iBMECs, widespread transcriptional dysregulation was observed in iBMECs compared to iPSCs. In addition, CAG expansion in iBMECs results in distinct responses to pathological and therapeutic perturbations including angiogenic factors, oxidative stress, and osmotic stress. In a tissue-engineered BBB model, iBMECs show subtle changes in phenotype, including differences in cell turnover and immune cell adhesion. Our results further support that CAG expansion in BMECs contributes to BBB dysfunction during HD.

| S-EPMC9245306 | biostudies-literature

Pericyte loss initiates microvascular dysfunction in the development of diastolic dysfunction

Project description:Microvascular dysfunction has been proposed to drive heart failure with preserved ejection fraction (HFpEF), but the initiating molecular and cellular events are largely unknown. Our objective was to determine when microvascular alterations in HFpEF begin, how they contribute to disease progression, and how pericyte dysfunction plays a role herein. We aimed to assess microvascular dysfunction with respect to the development of cardiac dysfunction, in the Zucker fatty and spontaneously hypertensive (ZSF1) obese rat model of HFpEF at three time points: 6, 14, and 21 weeks of age. We found that pericyte loss was the earliest and strongest microvascular change, occurring before prominent echocardiographic signs of diastolic dysfunction were present. Pericytes were shown to be less proliferative and had a disrupted morphology at 14 weeks in the obese ZSF1 animals, who also exhibited an increased capillary luminal diameter and disrupted endothelial junctions. Pericytes exposed to oxidative stress in vitro showed downregulation of cell cycle associated pathways, and induced a pro-inflammatory state in endothelial cells upon co-culture. We propose pericytes are important for maintaining endothelial cell function, where loss of pericytes enhances the reactivity of endothelial cells to inflammatory signals and promotes microvascular dysfunction, thereby accelerating the development of HFpEF.

2023-12-29 | GSE251995 | GEO

SARS-CoV-2 causes dysfunction in human iPSC-derived brain microvascular endothelial like cells potentially by signal modulation

Project description:SARS-CoV-2 is considered to affect the central nervous system (CNS) by interacting with the blood–brain barrier (BBB), which is defined by tight junctions that seal paracellular gaps between brain microvascular endothelial like cells (BMECs). Although SARS-CoV-2 infection of BMECs has been reported, the mechanism has not been fully elucidated. Here, we investigated the mechanism using iPSC derived brain microvascular endothelial like cells (iPSC-BMELCs). We observed that iPSC-BMELCs were infected with SARS-CoV-2, which resulted in inflammatory responses. RNA-seq analysis revealed that SARS-CoV-2 modulated the expression of signal molecules in iPSC-BMELCs. These findings suggest that SARS-CoV-2 infection causes BBB dysfunction in humans.

2024-02-01 | GSE254309 | GEO

RNA sequencing of human iPSC-derived brain microvascular endothelial cells.

Project description:Induced pluripotent stem cells were differentiated to brain microvascular endothelial cells (BMECs) using previously published protocols with minor changes. RNA was collected from purified BMECs after barrier induction and submitted for sequencing.

2020-12-31 | E-MTAB-8802 | biostudies-arrayexpress

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Project description:Purpose: The goals of this study are to compare the transcriptomic profile (mRNA-seq) of HD and control patient iPSC-derived brain microvascular endotheial cells to identify alterations in gene expression. Methods: RNA were isolated from HD and control iPSC-derived brain microvascular endothelial cells. mRNAseq using Illumina TruSeq mRNA PolyA+ v2 lib prep and HiSeq 2500. Statistical difference in mRNA levels were calculated with subsequent GO and pathway analysis. Results: mRNAseq and statistical analysis revealed differentially expressed genes between HD and control iPSC-derived brain microvascular endothelial cells. Conclusions: Our study shows differentially expressed genes between HD and control iPSC-derived brain microvascular endothelial cells, and reveals gene networks that are relevant to the mechanism of HD pathogenesis.

2017-05-16 | GSE97100 | GEO

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Isogenic human iPSC Parkinson's model shows nitrosative stress-induced dysfunction in MEF2-PGC1? transcription.

Project description:Parkinson's disease (PD) is characterized by loss of A9 dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). An association has been reported between PD and exposure to mitochondrial toxins, including environmental pesticides paraquat, maneb, and rotenone. Here, using a robust, patient-derived stem cell model of PD allowing comparison of A53T ?-synuclein (?-syn) mutant cells and isogenic mutation-corrected controls, we identify mitochondrial toxin-induced perturbations in A53T ?-syn A9 DA neurons (hNs). We report a pathway whereby basal and toxin-induced nitrosative/oxidative stress results in S-nitrosylation of transcription factor MEF2C in A53T hNs compared to corrected controls. This redox reaction inhibits the MEF2C-PGC1? transcriptional network, contributing to mitochondrial dysfunction and apoptotic cell death. Our data provide mechanistic insight into gene-environmental interaction (GxE) in the pathogenesis of PD. Furthermore, using small-molecule high-throughput screening, we identify the MEF2C-PGC1? pathway as a therapeutic target to combat PD.

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RNA-seq analysis of iPSC-derived brain microvascular endothelial cells following long-term cryopreservation

Project description:We report changes in gene expression from iPSC to iPSC-derived brain microvascular endothelial cells (dhBMECs) and from one-year cryopreservation of dhBMECs.

2020-06-08 | GSE151976 | GEO

WGS of KCNQ2 R201C patient derived iPSC and its isogenic line

Project description:Using prime editing, we generated an isogenic line of an iPSC line of an individual with a pathogenic KCNQ2 R201C mutation. WGS on the mutant line and two isogenic clones was performed to identify potential off target effects

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