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Patient-specific and Gene-corrected Induced Pluripotent Stem Cell-derived Endothelial Cells Elucidate Single-cell Phenotype of Pulmonary Veno-occlusive Disease

ABSTRACT: Patient-specific and Gene-corrected Induced Pluripotent Stem Cell-derived Endothelial Cells Elucidate Single-cell Phenotype of Pulmonary Veno-occlusive Disease

PROVIDER: PRJNA891628 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21943907_1.fastq.gz	Fastqsanger.gz
	SRR21943907_2.fastq.gz	Fastqsanger.gz
	SRR21943908_1.fastq.gz	Fastqsanger.gz
	SRR21943908_2.fastq.gz	Fastqsanger.gz
	SRR21943909_1.fastq.gz	Fastqsanger.gz

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Patient-specific and Gene-corrected Induced Pluripotent Stem Cell-derived Endothelial Cells Elucidate Single-cell Phenotype of Pulmonary Veno-occlusive Disease

Project description:PVOD is a rare form of pulmonary hypertension characterized by the preferential remodeling of the pulmonary venules. Hereditary PVOD is caused by biallelic variants of the EIF2AK4 gene. Three PVOD patients who carried the compound heterozygous variants of EIF2AK4 and two healthy controls were recruited and iPSCs were generated from human peripheral blood mononuclear cells (PBMCs). The EIF2AK4 c.2965C>T variant (PVOD#1), c.3460A>T variant (PVOD#2) and c.4832_4833insAAAG variant (PVOD#3) were corrected by CRISPR/Cas9 in PVOD-iPSCs to generate isogenic controls and gene-corrected-iPSCs (GC-iPSCs). PVOD-iPSC-ECs exhibited a decrease in GCN2 protein and mRNA expression, when compared to control and GC-ECs. PVOD-ECs exhibited an abnormal endothelial cell phenotype featured by excessive proliferation and angiogenesis. The abnormal phenotype of PVOD-ECs was normalized by AKT inhibitors AZD5363 and MK2206. These findings help elucidate the underlying molecular mechanism of PVOD in humans, and identify promising therapeutic drugs for treating the disease

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Differential Expression Profile of MicroRNAs and Tight Junction in Lung Tissue of Rat with Mitomycin-C Induced Pulmonary Veno-Occlusive Disease

Project description:Pulmonary veno-occlusive disease (PVOD) is characterized by increased pulmonary vascular resistance. Currently, there is a lack of effective treatment. It is of great significance to explore molecular targets for treatment of the disease. This study investigated the differentially expressed profile of miRNAs and tight junction in the lung tissue of rats with mitomycin-C induced PVOD.

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Patient-specific and gene-corrected induced pluripotent stem cell-derived endothelial cells elucidate single-cell phenotype of pulmonary veno-occlusive disease.

Project description:Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension characterized by the preferential remodeling of the pulmonary venules. Hereditary PVOD is caused by biallelic variants of the EIF2AK4 gene. Three PVOD patients who carried the compound heterozygous variants of EIF2AK4 and two healthy controls were recruited and induced pluripotent stem cells (iPSCs) were generated from human peripheral blood mononuclear cells (PBMCs). The EIF2AK4 c.2965C>T variant (PVOD#1), c.3460A>T variant (PVOD#2), and c.4832_4833insAAAG variant (PVOD#3) were corrected by CRISPR-Cas9 in PVOD-iPSCs to generate isogenic controls and gene-corrected-iPSCs (GC-iPSCs). PVOD-iPSC-endothelial cells (ECs) exhibited a decrease in GCN2 protein and mRNA expression when compared with control and GC-ECs. PVOD-ECs exhibited an abnormal EC phenotype featured by excessive proliferation and angiogenesis. The abnormal phenotype of PVOD-ECs was normalized by protein kinase B inhibitors AZD5363 and MK2206. These findings help elucidate the underlying molecular mechanism of PVOD in humans and to identify promising therapeutic drugs for treating the disease.

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Essential role of Protein kinase R in the pathogenesis of pulmonary veno-occlusive disease

Project description:Pulmonary veno-occlusive disease (PVOD) is a rare and severe form of pulmonary arterial hypertension, characterized by progressive obstruction of small pulmonary vessels and a lack of effective therapeutic options. Our previous research, utilizing a mitomycin C (MMC)-induced rat model, demonstrated that activation of the integrated stress response (ISR) via protein kinase R (PKR) is a critical driver of endothelial dysfunction and pulmonary vascular remodeling. However, it remains unclear whether PKR is the sole mediator of ISR activation and the pathogenesis of PVOD under the MMC treatment. In this study, we administered the same dose of MMC used in rats to control (Ctrl) and PKR knockout (KO) mice. Consistent with observations in rats, Ctrl mice exhibited ISR activation in the vascular endothelium and rapidly developed vascular remodeling in both arteries and veins following MMC treatment. In contrast, KO mice showed no evidence of ISR activation or vascular remodeling under same conditions. Proteomic analysis revealed that the PKR-ISR axis perturbs proteostasis in Ctrl mice but not in KO mice. These findings highlight the essential role of PKR-mediated ISR activation and the disruption of proteostasis in the pathogenesis of PVOD, placing PKR as a promising therapeutic target for this disease.

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Project description:A pig model of human radiation-induced veno-occlusive liver disease reveals ferroptosis as a therapeutic target

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A pig model of human radiation-induced veno-occlusive liver disease reveals ferroptosis as a therapeutic target

Project description:Radiation-induced liver disease (RILD) is a significant complication of radiotherapy and radiation-based preconditioning for cell transplantation. Despite its importance, understanding its pathogenesis and developing effective therapies have been challenging due to the lack of an appropriate animal model that faithfully reproduces the pathological hallmarks of RILD. In this study, given their anatomical and physiological similarities to humans, we used Bama miniature pigs to establish a reliable large-animal model of RILD through a dose-escalation study using hypofractionated stereotactic body radiation therapy. Pigs receiving 40 Gy radiation developed RILD symptoms and exhibited significant liver dysfunction within 4 weeks, closely resembling human disease progression. Moreover, the pigs developed key pathological RILD hallmarks, including hepatic veno-occlusive disease, centrilobular necrosis, liver fibrosis, and compromised liver regeneration. Through single-nucleus RNA sequencing (snRNA-seq) and histological analyses, we found that hepatocytes in the RILD pig model underwent ferroptosis. Notably, treating these pigs with the ferroptosis inhibitor Liproxstatin-1 after irradiation significantly reversed the symptoms and pathological features of RILD and enhanced liver regeneration, particularly by promoting the proliferation of hepatocytes and endothelial cells. These results underscore the role of hepatocyte ferroptosis as a pivotal driver of RILD and highlight its potential as a therapeutic target. Our study provides a valuable large-animal platform for advancing the understanding and treatment of RILD, as well as optimizing radiation-based therapies and preconditioning strategies.

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Gene expression in occlusive vein grafts following CABG of human

Project description:To further understand the mechanism approach to occlusive vein grafts, we have employed RNA-seq to identify key genes in occlusive venin grafts following CABG in human. The occluded vein graft and intraoperative spare great saphenous vein of patients undergoing clinical re-coronary artery bypass grafting were obtained for RNA-seq. The sequencing results were cleaned and bioinformatics annlysis was conducted by using WGCNA and a variety of online databases and software. The key genes or proteins affecting the occurrence of vein graft restenosis were screened out(ITGB2), and the expression level of the target genes or proteins was verified by real-time PCR and Western blot. And to further learn the effect of ITGB2 in human primary venous smooth muscle cells, ITGB2 gene was silenced by SiRNA. The effect of ITGB2 silencing on proliferation, migration and invasion of venous smooth muscle cells after PDGF-BB-stimulation were detected by Edu assay, scrathch experiment and transwell experiment. And Edu assay showed that ITGB2 silencing could inhibit the proliferation of PDGF-BB sitmulated smooth muscle cells. Scratch assay showed that ITGB2 silencing inhibited the migration of PDGF-BB stimulated smooth muscle cells. Transwell assay showed that ITGB2 silencing significantly inhibited the invasion of PDGF-BB stimulated smooth muscle cells. It is indicated that ITGB2 was the key gene in vein graft restenosis,and may be the potential treatment target in restenosis patients.

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Project description:Arterial occlusive diseases are major causes of morbidity and mortality. Blood flow to the affected tissue must be restored quickly if viability and function are to be preserved. Collaterals are artery-to-artery or arteriole-to-arteriole interconnections that can bypass an occlusion by providing an alternative route for blood flow to the affected tissue. The increased flow and sheer stress initiate processes that result in the remodeling (arteriogenesis) of these vessels into efficient conductance arteries. Here we report that the mixed-lineage kinase (MLK) pathway activates cJun NH2-terminal kinase (JNK) in endothelial cells. Disruption of Mlk2/3 or Jnk1/2 genes caused severe blockade of blood flow and failure to recover in the femoral artery ligation model of hindlimb ischemia because of abnormal collateral arteries. We show that the MLK-JNK pathway is essential for patterning and maturation of collateral arteries during development, but this pathway is not required for angiogenesis or arteriogenesis in adults. JNK in endothelial cells promotes Delta-like 4-induced Notch signaling and suppresses excessive sprouting angiogenesis during development. This function of the MLK-JNK pathway contributes to normal formation of native collateral arteries. The MLK-JNK pathway is therefore a key regulatory mechanism for vascular development. These data highlight the crucial importance of the collateral circulation in the response to arterial occlusive diseases. RNA-seq analysis of mouse lung endothelial cells (MLEC) of the following genotypes Cdh5-Cre+ Jnk1+/+ Jnk2+/+ Jnk3-/-(ECtrl), Cdh5-Cre- Jnk1LoxP/LoxP Jnk2LoxP/LoxP Jnk3-/- (EfCtrl), and Cdh5-Cre+ Jnk1LoxP/LoxP Jnk2LoxP/LoxP Jnk3-/- (E3KO). Three separate samples from mouse lung endothelial cells of each genotype were analyzed.

2016-08-09 | E-GEOD-71159 | biostudies-arrayexpress

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