title: Stem cell factor and granulocyte colony-stimulating factor exhibit therapeutic effects in a mouse model of CADASIL.
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.
authors.affiliation: Department of Neurology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA.
authors.forename: Xiao-Yun
authors.initials: XY
authors.lastname: Liu
authors.affiliation: Department of Neurology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Gonzalez-Toledo
authors.affiliation: Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA.
authors.forename: Austin
authors.initials: A
authors.lastname: Fagan
authors.affiliation: Department of Anatomy, Capital Medical University, Beijing 100069, China; Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing 100069, China.
authors.forename: Wei-Ming
authors.initials: WM
authors.lastname: Duan
authors.affiliation: Department of Neurosurgery, State University of New York, Upstate Medical University, Syracuse, NY 13210, USA.
authors.forename: Yanying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Neurology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Neurology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA.
authors.forename: Chun-Shu
authors.initials: CS
authors.lastname: Piao
authors.affiliation: Department of Neurology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA.
authors.forename: Lila
authors.initials: L
authors.lastname: Nelson
authors.affiliation: Department of Neurology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA; Department of Cellular Biology and Anatomy, 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; Department of Neurobiology, Capital Medical University, Beijing 100069, China. Electronic address: ZHAOL@upstate.edu.
authors.forename: Li-Ru
authors.initials: LR
authors.lastname: Zhao
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D046589:CADASIL / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics / Q000601:surgery; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics; D019089:Stem Cell Factor / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D019089:Stem Cell Factor; D016179:Granulocyte Colony-Stimulating Factor; D053148:Caspase 3
keywords: Angiogenesis; Apoptosis; Bone marrow-derived cell; CAA; CADASIL; G-CSF; Neurogenesis; SCF; Vascular smooth muscle cell