RNA sequencing analysis of neural crest-derived vascular smooth muscle cells differentiated from CADASIL patient and control iPSCs.

NOTCH3 variants cause CADASIL (cerebral autosomal dominant arteriopathy and subcortical infarcts and leukoencephalopathy), the most common monogenetic form of small vessel disease (SVD) and vascular dementia (VaD). Although CADASIL is well recognized clinically, the molecular mechanisms underlying its pathogenesis remain poorly understood, and no targeted therapies are currently available. NOTCH3 is predominantly expressed in vascular smooth muscle cells (VSMCs), which originate from distinct embryonic lineages. Using human induced pluripotent stem cell (iPSC) models, we generated origin-specific VSMCs and found that cerebral, but not peripheral, VSMC-mimics are selectively vulnerable to NOTCH3 variants. In this study, we focused on the neural crest-derived VSMCs and performed RNA-seq to compare gene expression profiles between wild-type and CADASIL patient iPSC-derived neural crest VSMCs.