Patient-Specific iPSC Model of a Genetic Vascular Dementia Syndrome Reveals Failure of Mural Cells to Stabilize Capillary Structures

Stem Cell Reports. 2019 Nov 12;13(5):817-831. doi: 10.1016/j.stemcr.2019.10.004. Epub 2019 Oct 31.


CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most common form of genetic stroke and vascular dementia syndrome resulting from mutations in NOTCH3. To elucidate molecular mechanisms of the condition and identify drug targets, we established a patient-specific induced pluripotent stem cell (iPSC) model and demonstrated for the first time a failure of the patient iPSC-derived vascular mural cells (iPSC-MCs) in engaging and stabilizing endothelial capillary structures. The patient iPSC-MCs had reduced platelet-derived growth factor receptor β, decreased secretion of the angiogenic factor vascular endothelial growth factor (VEGF), were highly susceptible to apoptotic insults, and could induce apoptosis of adjacent endothelial cells. Supplementation of VEGF significantly rescued the capillary destabilization. Small interfering RNA knockdown of NOTCH3 in iPSC-MCs revealed a gain-of-function mechanism for the mutant NOTCH3. These disease mechanisms likely delay brain repair after stroke in CADASIL, contributing to the brain hypoperfusion and dementia in this condition, and will help to identify potential drug targets.

Keywords: CADASIL; NOTCH3; angiogenesis; genetic stroke; iPSC; iPSC disease model; notch signaling; pericytes; small vessel disease; vascular dementia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CADASIL / genetics
  • CADASIL / pathology*
  • Cells, Cultured
  • Dementia, Vascular / genetics
  • Dementia, Vascular / pathology*
  • Down-Regulation
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology*
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / pathology*
  • Mutation
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / pathology
  • Receptor, Notch3 / genetics
  • Receptor, Platelet-Derived Growth Factor beta / analysis
  • Receptor, Platelet-Derived Growth Factor beta / genetics


  • NOTCH3 protein, human
  • Receptor, Notch3
  • Receptor, Platelet-Derived Growth Factor beta