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

Neurobiology of Disease

Yanying Liu¹  Wei-Ming Duan²  Austin Fagan³  Maria E. Gonzalez-Toledo⁴  Lila Nelson⁴  Xiao-Yun Liu⁴  Bin Li⁴  Chun-Shu Piao⁴  Li-Ru Zhao⁴  Siyuan Zhang⁵ 

[1] Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing 100069, China;Department of Anatomy, Capital Medical University, Beijing 100069, China;Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA;Department of Neurology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA;Department of Neurosurgery, State University of New York, Upstate Medical University, Syracuse, NY 13210, USA;

关键词: CADASIL;    SCF;    G-CSF;    CAA;    Vascular smooth muscle cell;    Apoptosis;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown