Stem cell factor and granulocyte colony-stimulating factor exhibit therapeutic effects in a mouse model of CADASIL

Xiao Yun Liu, Maria E. Gonzalez-Toledo, Austin Fagan, Wei Ming Duan, Yanying Liu, Siyuan Zhang, Bin Li, Chun Shu Piao, Lila Nelson, Li Ru Zhao*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a Notch3 dominant mutation-induced cerebral small vascular disease, is characterized by progressive degeneration of vascular smooth muscle cells (vSMCs) of small arteries in the brain, leading to recurrent ischemic stroke, vascular dementia and death. To date, no treatment can stop or delay the progression of this disease. Herein, we determined the therapeutic effects of stem cell factor (SCF) in combination with granulocyte colony-stimulating factor (G-CSF) (SCF. +. G-CSF) in a mouse model of CADASIL carrying the human mutant Notch3 gene. SCF. +. G-CSF was subcutaneously administered for 5. days and repeated 4 times with 1-4. month intervals. We found through water maze testing that SCF. +. G-CSF treatment improved cognitive function. SCF. +. G-CSF also attenuated vSMC degeneration in small arteries, increased cerebral blood vascular density, and inhibited apoptosis in CADASIL mice. We also discovered that loss of cerebral capillary endothelial cells and neural stem cells/neural progenitor cells (NSCs/NPCs) occurred in CADASIL mice. SCF. +. G-CSF treatment inhibited the CADASIL-induced cell loss in the endothelia and NSCs/NPCs and promoted neurogenesis. In an in vitro model of apoptosis, SCF. +. G-CSF prevented apoptotic cell death in vSMCs through AKT signaling and by inhibiting caspase-3 activity. These data suggest that SCF. +. G-CSF restricts the pathological progression of CADASIL. This study offers new insights into developing therapeutic strategies for CADASIL.

Original languageEnglish (US)
Pages (from-to)189-203
Number of pages15
JournalNeurobiology of Disease
Volume73
DOIs
StatePublished - Jan 1 2015

Keywords

  • Angiogenesis
  • Apoptosis
  • Bone marrow-derived cell
  • CAA
  • CADASIL
  • G-CSF
  • Neurogenesis
  • SCF
  • Vascular smooth muscle cell

ASJC Scopus subject areas

  • Neurology

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