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

Liu, Xiaoyun; Gonzalez-Toledo, Maria E.; Fagan, Austin; Duan, Wei; Li, Yanying; Zhang, Siyuan; Li, Bin; Piao, Chun Shu; Nelson, Lila; Zhao, Li

doi:10.1016/j.nbd.2014.09.006

Cited by 30 publications

(32 citation statements)

References 66 publications

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“…The first (C2; G-CSF, IL-10, and RANTES) included cytokines that were higher in LPS-treated mice that express APOE4 (E4FAD+ and E4FAD− mice) compared to the PBS group. RANTES promotes angiogenesis (Wang et al., 2006; Matsuo et al., 2009; Suffee et al., 2012; Liu et al., 2015a), while G-CSF and IL-10 have been demonstrated to both protect/maintain and disrupt the vasculature (Kohno et al., 2003; Dace et al., 2008; Tura et al., 2010; Kawabe et al., 2011; Alexandrakis et al., 2015; Cates et al., 2015; Liu et al., 2015a, 2015b; Wei et al., 2017). Therefore, it is possible that the C2 cytokines initiated angiogenic signaling in E4FAD+ and E4FAD− mice, without maturing into stable vessels, or induced direct brain endothelial cell disruption in a chronic setting.…”

Section: Discussionmentioning

confidence: 99%

Peripheral Inflammation,Apolipoprotein E4, and Amyloid-β Interact to Induce Cognitive and Cerebrovascular Dysfunction

et al. 2017

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Cerebrovascular dysfunction is rapidly reemerging as a major process of Alzheimer’s disease (AD). It is, therefore, crucial to delineate the roles of AD risk factors in cerebrovascular dysfunction. While apolipoprotein E4 (APOE4), Amyloid-β (Aβ), and peripheral inflammation independently induce cerebrovascular damage, their collective effects remain to be elucidated. The goal of this study was to determine the interactive effect of APOE4, Aβ, and chronic repeated peripheral inflammation on cerebrovascular and cognitive dysfunction in vivo. EFAD mice are a well-characterized mouse model that express human APOE3 (E3FAD) or APOE4 (E4FAD) and overproduce human Aβ42 via expression of 5 Familial Alzheimer’s disease (5xFAD) mutations. Here, we utilized EFAD carriers [5xFAD+/−/APOE+/+ (EFAD+)] and noncarriers [5xFAD−/−/APOE+/+ (EFAD−)] to compare the effects of peripheral inflammation in the presence or absence of human Aβ overproduction. Low-level, chronic repeated peripheral inflammation was induced in EFAD mice via systemic administration of lipopolysaccharide (LPS; 0.5 mg/kg/wk i.p.) from 4 to 6 months of age. In E4FAD+ mice, peripheral inflammation caused cognitive deficits and lowered post-synaptic protein levels. Importantly, cerebrovascular deficits were observed in LPS-challenged E4FAD+ mice, including cerebrovascular leakiness, lower vessel coverage, and cerebral amyloid angiopathy-like Aβ deposition. Thus, APOE4, Aβ, and peripheral inflammation interact to induce cerebrovascular damage and cognitive deficits.

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Section: Discussionmentioning

confidence: 99%

Peripheral Inflammation,Apolipoprotein E4, and Amyloid-β Interact to Induce Cognitive and Cerebrovascular Dysfunction

et al. 2017

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“…SCF and G-CSF were also found to increase endothelial cells derived from bone marrow in murine brains following cerebral ischemia [105]. The combination of SCF and G-CSF has also exhibited an angiogenesis effect by reducing the apoptosis of vascular smooth muscle and increasing cerebral vascular density in a mouse model of leukoencephalopathy [106]. NF-κB has been shown to be necessary for the vascular remodeling effect of SCF and G-CSF therapy as blockage of NF-κB activation was found to reduce post-stroke functional restoration [107].…”

Section: Scfmentioning

confidence: 99%

Growth factor therapy sequesters inflammation in affording neuroprotection in cerebrovascular diseases

Nguyen

Aum

Mashkouri

et al. 2016

Expert Review of Neurotherapeutics

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In recent years, accumulating evidence has demonstrated the important role of inflammation in cerebrovascular diseases. The inflammation can last for a long period after the initial insult. Hence, modulation of the inflammation in a wider therapeutic window is a practical approach to treat these cerebrovascular diseases. Despite the acute upregulation of many growth factors after the injury, it is not sufficient to protect and to regenerate the brain. In this mini review, we discuss major growth factors and their beneficial properties to combat the inflammation in cerebrovascular diseases. Emerging biotechnologies that facilitate the therapeutic effects of growth factors are also discussed in an effort to provide insights into the future combination therapies incorporating both central and peripheral abrogation of inflammation. Strategies designed to robustly maintain upregulation of growth factors in the injured brain and the circulation may prove as a potent regenerative approach in sequestering neuroinflammation associated with cerebrovascular diseases.

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“…Using TghNotch3 R90c mice as a mouse model of CADASIL, we have revealed that mitochondrial damage and multiple large digestive lysosomes appear in the capillary pericytes of the brain, suggesting the involvement of autophagy in the degeneration of cerebral capillary pericytes in the CADASIL condition [25] . In addition, using the bone marrow transplantation approach to track bone marrow-derived cells, we have discovered that many cerebral capillaries in the brains of CADASIL mice are completely replaced by the bone marrow-derived endothelial cells, suggesting a progressive loss of cerebral capillary endothelial cells in CADASIL and the involvement of bone marrow-derived endothelial cells in the pathogenesis of CADASIL [26] In support of this notion, a significant reduction in circulating endothelial progenitor cells (EPCs) has been found in the CADASIL patients with infarcts and dementia [27] . It is therefore plausible that the reduction of circulating EPCs in CADASIL may be due to the persistent consumption of EPCs to replace the damaged endothelium during the progressive degeneration of cerebral capillaries.…”

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confidence: 99%

“…It is therefore plausible that the reduction of circulating EPCs in CADASIL may be due to the persistent consumption of EPCs to replace the damaged endothelium during the progressive degeneration of cerebral capillaries. Furthermore, the neural stem cells (NSCs) and neurogenesis in the neurogenic regions of TghNotch3 R90c mice are remarkably decreased as compared to age-matched wildtype mice [26] , indicating the impairments of NSC maintenance and differentiation in the condition of CADASIL. A large body of evidence has shown that microvascularture, blood flow and hemodynamics in the neurogenic regions play a crucial role in regulating NSC maintenance, proliferation and differentiation [28–38] .…”

mentioning

confidence: 99%

“…We therefore postulate that CADASIL-associated degeneration of cerebral capillaries provides an unfavorable microenvironment for NSC maintenance and differentiation. Finally, we have also found that TghNotch3 R90c mice at ages of 11 and 19 months show the impairments ofspatial learning and memory in a water maze test when compared with age-matched wildtype mice [26] . The impaired cognitive function may be associated with the cerebral vascular degeneration caused by the CADASIL-related Notch3 mutation, because vSMC degeneration and cerebral vascular dysfunction have previously been found in 10-month-old TghNotch3 R90c mice [21, 23] …”

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confidence: 99%

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Novel pathological features and potential therapeutic approaches for CADASIL: insights obtained from a mouse model of CADASIL

Liu

Gonzalez-Toledo

Fagan

et al. 2015

Ther Targets Neurol Dis

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common condition of hereditary stroke and vascular dementia. CADASIL is caused by Notch3 mutation, leading to progressive degeneration of vascular smooth muscle cells (vSMCs) of the small arteries in the brain. However, the pathogenesis of CADASIL remains largely unknown, and treatment that can stop or delay the progression of CADASIL is not yet available. Using both wild type mice and transgenic mice carrying the human mutant Notch3 gene (CADASIL mice), we have recently characterized the pathological features of CADASIL and determined the therapeutic efficacy of two hematopoietic growth factors, stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) in CADASIL. Our findings have revealed novel pathological changes in the endothelium of cerebral capillaries and in the neural stem cells (NSCs). We have also observed the impairment of cognitive function in CADASIL mice. Moreover, SCF+G-CSF treatment improves cognitive function, inhibits Notch3 mutation-induced vSMC degeneration, cerebral blood bed reduction, cerebral capillary damage, and NSC loss, and increases neurogenesis and angiogenesis. Here we compile an overview of our recently published studies, which provide new insights into understanding the pathogenesis of CADASIL and developing therapeutic strategies for this devastating neurological disease.

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

Cited by 30 publications

References 66 publications

Peripheral Inflammation,Apolipoprotein E4, and Amyloid-β Interact to Induce Cognitive and Cerebrovascular Dysfunction

Peripheral Inflammation,Apolipoprotein E4, and Amyloid-β Interact to Induce Cognitive and Cerebrovascular Dysfunction

Growth factor therapy sequesters inflammation in affording neuroprotection in cerebrovascular diseases

Novel pathological features and potential therapeutic approaches for CADASIL: insights obtained from a mouse model of CADASIL

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