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.

Suning Ping,Xiaoyun Liu,Xuecheng Qiu,Maria E Gonzalez-Toledo,Li-Ru Zhao

doi:10.3389/fcell.2020.627733

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.

Highlights

MATERIALS AND METHODSCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic cause of stroke and vascular dementia in adults (Chabriat et al, 2009)
This study aims to determine the distribution of capillary thrombosis in the brain, the existence of cerebral capillary thrombosis-caused ischemic neuron loss, and the efficacy of stem cell factor (SCF)+granulocyte colony-stimulating factor (G-CSF) treatment in reducing microvascular ischemic damage in TgNotch3R90C mice
We found that the occluded capillaries were filled with green fluorescent protein (GFP) positive bone marrow-derived blood cells (Figures 1C–G), indicating that capillary thrombosis occurs in the brains of TgNotch3R90C mice

Summary

Introduction

MATERIALS AND METHODSCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic cause of stroke and vascular dementia in adults (Chabriat et al, 2009). CADASIL is caused by mutations in the NOTCH3 gene (Joutel et al, 1996). NOTCH3-encoded Notch receptor is predominantly expressed in vascular smooth muscle cells (VSMCs) of small arteries (Wang et al, 2012) and pericytes of capillaries (Wang et al, 2014). Due to the specific distribution of Notch, the typical pathologies in the brain are mainly found in small arteries and capillaries in both CADASIL patients and mouse models (Joutel, 2011). Pathological changes in endothelial cells (ECs) have been observed in CADASIL patients and the TgNotch3R90C mouse model of CADASIL (Ruchoux and Maurage, 1998; Ping et al, 2018, 2019). Endothelial dysfunction is crucially involved in vascular ischemia as ECs shift from an anti-thrombotic to a prothrombotic stage when their function is dysregulated (Yau et al, 2015)

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