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

[cadasil]

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL ), a Notch 3 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 Notch 3 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 .