iPSC-Derived Endothelial Cells Reveal LDLR Dysfunction and Dysregulated Gene Expression Profiles in Familial...

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.