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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. | LitMetric

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

Stem Cell Reports

State Key Laboratory of Cardiovascular Disease, Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Diagnostic Laboratory Service, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. Electronic address:

Published: December 2022

AI Article Synopsis

  • - Pulmonary veno-occlusive disease (PVOD) is a rare type of pulmonary hypertension linked to changes in the small veins of the lungs and is often inherited through mutations in the EIF2AK4 gene.
  • - Researchers created induced pluripotent stem cells (iPSCs) from patients with PVOD and corrected gene mutations using CRISPR-Cas9, yielding isogenic and gene-corrected cells.
  • - The study found that the endothelial cells from PVOD patients showed abnormal growth and blood vessel formation, which could be reversed with specific protein kinase B inhibitors, pointing to potential treatment options.

Article Abstract

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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9768576PMC
http://dx.doi.org/10.1016/j.stemcr.2022.10.014DOI Listing

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