Stem Cell Factor in Combination With Granulocyte Colony-Stimulating Factor Protects the Brain From Capillary Thrombosis-Induced Ischemic Neuron Loss in a Mouse Model of CADASIL

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) is a Notch3 mutation-induced cerebral small vessel disease, leading to recurrent ischemic stroke and vascular dementia. There is currently no treatment that can stop or delay CADASIL progression. We have demonstrated the efficacy of treatment with combined stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) (SCF+G-CSF) in reducing cerebral small vessel thrombosis in a TgNotch3R90C mouse model of CADASIL. However, it remains unknown whether SCF+G-CSF treatment protects neurons from microvascular thrombosis-induced ischemic damage. Using bone marrow transplantation to track thrombosis, we observed that capillary thrombosis was widely distributed in the cortex, striatum and hippocampus of 22-month-old TgNotch3R90C mice. However, the capillary thrombosis mainly occurred in the cortex. Neuron loss was seen in the area next to the thrombotic capillaries, and severe neuron loss was found in the areas adjacent to the thrombotic capillaries with bifurcations. SCF+G-CSF repeated treatment significantly attenuated neuron loss in the areas next to the thrombotic capillaries in the cortex of the 22-month-old TgNotch3R90C mice. Neuron loss caused by capillary thrombosis in the cerebral cortex may play a crucial role in the pathogenesis of CADASIL. SCF+G-CSF treatment ameliorates the capillary thrombosis-induced ischemic neuron loss in TgNotch3R90C mice. This study provides new insight into the understanding of CADASIL progression and therapeutic potential of SCF+G-CSF in neuroprotection under microvascular ischemia in CADASIL.

LMD: Cluster-Independent Multiscale Marker Identification in Single-cell RNA-seq Data

“…Modules associated with B lymphocytes are substantiated by the inclusion of genes with well-established roles in this differentiation process: Module 7, with genes Rag1 and Rag2, represents pro-B and pre-B cells, as these genes participate in the heavy and light chain rearrangement processes [22]; module 9, containing genes Ms4a1 and Cd22, pertains to B cell activation and regulation, marking both immature and mature B cells in the bone marrow [23,24]; module 10, which features genes Fcer2a, Ms4a4c, and Cxcr5, characterizes naive B cells [25][26][27]. We similarly identified at least 4 modules associated with granulopoiesis: module 45, exclusively expressed in granulopoietic cells and including the granulopoietic marker Fcnb [11,28]; module 44, featuring markers Camp and Ltf, both of which are found in granulocyte and granulopoietic cells [15]; module 41, specific to a subset of granulocytes and containing Retnlg and Cxcr2, which suggests a potential role in neutrophil migration and release [29,30]; lastly, module 43, characterized by genes implicated in pyroptosis and antigen processing such as Stfa2l1, Il1b, Gm5483, H2-Q10, and Irg1 [31][32][33][34], which may represent a rare granulocyte subgroup engaged in the immune response against intracellular pathogens.…”

Single cell RNA sequencing reveals immunomodulatory effects of stem cell factor and granulocyte colony-stimulating factor treatment in the brains of aged APP/PS1 mice

“…SCF and G-CSF also act directly on neurons, glia, and blood vessel cells [58, 59, 60], in the central nervous system. SCF and G-CSF treatment enhances angiogenesis, neural survival, neurite outgrowth, synaptogenesis, and neurogenesis, and reduces neuro-inflammation in several models of neurodegenerative diseases, neurological disorders, and brain trauma [61, 62, 63, 64, 65, 66, 67]. In AD patient populations, plasma levels of SCF and G-CSF are significantly reduced [68, 69].…”