Stem cell factor and granulocyte colony-stimulating factor exhibit therapeutic effects in a mouse model of CADASIL
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.
Publication Source (Journal or Book title)
Neurobiology of Disease
Liu, X., Gonzalez-Toledo, M., Fagan, A., Duan, W., Liu, Y., Zhang, S., Li, B., Piao, C., Nelson, L., & Zhao, L. (2015). Stem cell factor and granulocyte colony-stimulating factor exhibit therapeutic effects in a mouse model of CADASIL. Neurobiology of Disease, 73, 189-203. https://doi.org/10.1016/j.nbd.2014.09.006