Modeling CADASIL vascular pathologies with patient-derived induced pluripotent stem cells

Area of Science:

• Neuroscience
• Genetics
• Stem Cell Biology

Background:

• Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare genetic cerebrovascular disorder.
• The precise cellular and molecular mechanisms driving CADASIL pathogenesis are not fully understood.
• NOTCH3 mutations are the known cause of CADASIL.

Purpose of the Study:

• To investigate the cellular and molecular mechanisms underlying CADASIL using patient-derived induced pluripotent stem cells (iPSCs).
• To identify potential therapeutic targets for CADASIL by modeling disease phenotypes in vitro.
• To differentiate between the cellular effects of the NOTCH3 mutation in vascular smooth muscle cells versus vascular endothelial cells.

Main Methods:

• Generation of non-integrative iPSCs from CADASIL patient fibroblasts with a specific NOTCH3 mutation (c.3226C>T, p.R1076C).
• Differentiation of iPSCs into vascular smooth muscle cells (VSMCs) and vascular endothelial cells (VECs).
• Analysis of gene expression, signaling pathways (NOTCH, NF-κB), cytoskeleton organization, and cell proliferation in differentiated cells.

Main Results:

• CADASIL-derived VSMCs exhibited altered gene expression, including activation of NOTCH and NF-κB signaling pathways, cytoskeleton disorganization, and increased proliferation.
• No significant abnormalities were observed in CADASIL-derived VECs.
• Inhibition of the NOTCH pathway reduced the aberrant upregulation of NF-κB target genes in CADASIL VSMCs.

Conclusions:

• The iPSC-based model successfully recapitulated key cellular phenotypes associated with CADASIL in VSMCs.
• The study implicates the NOTCH and NF-κB signaling pathways in CADASIL pathogenesis.
• Targeting the NOTCH pathway presents a potential therapeutic strategy for mitigating CADASIL-related vascular smooth muscle cell dysfunction.