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Updated: Jul 5, 2025
A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes
Published on: September 15, 2018
iPSC-Derived Endothelial Cells Reveal LDLR Dysfunction and Dysregulated Gene Expression Profiles in Familial
Irina S Zakharova1, Alexander I Shevchenko1, Mhd Amin Arssan1
1Federal Research Centre Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia.
Insights
Familial hypercholesterolemia (FH) involves low-density lipoprotein receptor (LDLR) defects, impacting endothelial cells. Our study reveals LDLR defects in FH endothelial cells increase inflammation and oxidative stress susceptibility, contributing to cardiovascular disease.
Area of Science:
- Cardiovascular Biology
- Genetics
- Stem Cell Biology
Background:
- Defects in the low-density lipoprotein receptor (LDLR) are a primary cause of familial hypercholesterolemia (FH).
- LDLR deficiency elevates blood cholesterol, promoting vascular cell damage via oxidative stress and inflammation.
- Understanding differences in endothelial cells with normal versus defective LDLR is crucial for FH research.
Purpose of the Study:
- To investigate the molecular and functional distinctions of endothelial cells derived from induced pluripotent stem cells (iPSCs) of healthy individuals and FH patients.
- To characterize the impact of pathogenic LDLR alleles on endothelial cell phenotype and gene expression.
Main Methods:
- Generated endothelial cells from iPSCs of healthy donors and FH patients with pathogenic LDLR alleles.
- Assessed LDLR protein levels and low-density lipoprotein (LDL) uptake in both cell types.
- Performed RNA sequencing (RNA-seq) on mutant LDLR iPSC-derived endothelial cells (iPSC-ECs) to analyze transcriptome profiles.
Main Results:
- Normal iPSC-ECs exhibited mature LDLR protein, while FH iPSC-ECs showed reduced mature LDLR and abolished LDL uptake.
- RNA-seq revealed distinct transcriptome profiles in FH iPSC-ECs, with downregulated genes in monocarboxylic acid transport, exocytosis, and cell adhesion.
- Upregulated pathways in FH iPSC-ECs were associated with cell secretion and leukocyte activation.
Conclusions:
- LDLR defects in endothelial cells heighten susceptibility to inflammation and oxidative stress.
- These cellular changes, combined with high cholesterol, may accelerate endothelial dysfunction and atherosclerosis progression in FH.
- Findings provide insights into FH pathogenesis and potential therapeutic targets for cardiovascular disease.
Abstract:
Defects in the low-density lipoprotein receptor (LDLR) are associated with familial hypercholesterolemia (FH), manifested by atherosclerosis and cardiovascular disease. LDLR deficiency in hepatocytes leads to elevated blood cholesterol levels, which damage vascular cells, especially endothelial cells, through oxidative stress and inflammation. However, the distinctions between endothelial cells from individuals with normal and defective LDLR are not yet fully understood. In this study, we obtained and examined endothelial derivatives of induced pluripotent stem cells (iPSCs) generated previously from conditionally healthy donors and compound heterozygous FH patients carrying pathogenic LDLR alleles. In normal iPSC-derived endothelial cells (iPSC-ECs), we detected the LDLR protein predominantly in its mature form, whereas iPSC-ECs from FH patients have reduced levels of mature LDLR and show abolished low-density lipoprotein uptake. RNA-seq of mutant LDLR iPSC-ECs revealed a unique transcriptome profile with downregulated genes related to monocarboxylic acid transport, exocytosis, and cell adhesion, whereas upregulated signaling pathways were involved in cell secretion and leukocyte activation. Overall, these findings suggest that LDLR defects increase the susceptibility of endothelial cells to inflammation and oxidative stress. In combination with elevated extrinsic cholesterol levels, this may result in accelerated endothelial dysfunction, contributing to early progression of atherosclerosis and other cardiovascular pathologies associated with FH.
