scholarly journals Stem Cell Factor in Combination with Granulocyte Colony-Stimulating Factor reduces Cerebral Capillary Thrombosis in a Mouse Model of CADASIL

2018 ◽  
Vol 27 (4) ◽  
pp. 637-647 ◽  
Author(s):  
Suning Ping ◽  
Xuecheng Qiu ◽  
Maria E Gonzalez-Toledo ◽  
Xiaoyun Liu ◽  
Li-Ru Zhao
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Mouse Model ◽  
Stem Cell Factor ◽  
Granulocyte Colony Stimulating Factor ◽  
Cerebral Thrombosis ◽  
Colony Stimulating Factor ◽  
Cerebral Capillaries ◽  
Cerebral Capillary ◽  
Stimulating Factor

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a cerebral small vascular disease caused by NOTCH3 mutation-induced vascular smooth muscle cell (VSMC) degeneration, leading to ischemic stroke and vascular dementia. Our previous study has demonstrated that repeated treatment with a combination of stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) reduces VSMC degeneration and cerebral endothelial cell (EC) damage and improves cognitive function in a mouse model of CADASIL (TgNotch3R90C). This study aimed to determine whether cerebral thrombosis occurs in TgNotch3R90C mice and whether repeated SCF+G-CSF treatment reduces cerebral thrombosis in TgNotch3R90C mice. Using the approaches of bone marrow transplantation to track bone marrow-derived cells and confocal imaging, we observed bone marrow-derived blood cell occlusion in cerebral small vessels and capillaries (thrombosis). Most thrombosis occurred in the cerebral capillaries (93% of total occluded vessels), and the thrombosis showed an increased frequency in the regions of capillary bifurcation. Degenerated capillary ECs were seen inside and surrounding the thrombosis, and the bone marrow-derived ECs were also found next to the thrombosis. IgG extravasation was seen in and next to the areas of thrombosis. SCF+G-CSF treatment significantly reduced cerebral capillary thrombosis and IgG extravasation. These data suggest that the EC damage is associated with thrombosis and blood–brain barrier leakage in the cerebral capillaries under the CADASIL-like condition, whereas SCF+G-CSF treatment diminishes these pathological alterations. This study provides new insight into the involvement of cerebral capillary thrombosis in the development of CADASIL and potential approaches to reduce the thrombosis, which may restrict the pathological progression of CADASIL.

scholarly journals The combination of granulocyte colony-stimulating factor and stem cell factor significantly increases the number of bone marrow–derived endothelial cells in brains of mice following cerebral ischemia

Blood ◽  
2008 ◽  
Vol 111 (12) ◽  
pp. 5544-5552 ◽  
Author(s):  
Zsuzsanna E. Toth ◽  
Ronen R. Leker ◽  
Tal Shahar ◽  
Sandra Pastorino ◽  
Ildiko Szalayova ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Stem Cell ◽  
Stem Cell Factor ◽  
Fluorescent Protein ◽  
Fold Increase ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Hematopoietic Stem ◽  
Stimulating Factor

Abstract Granulocyte colony-stimulating factor (G-CSF) induces proliferation of bone marrow–derived cells. G-CSF is neuroprotective after experimental brain injury, but the mechanisms involved remain unclear. Stem cell factor (SCF) is a cytokine important for the survival and differentiation of hematopoietic stem cells. Its receptor (c-kit or CD117) is present in some endothelial cells. We aimed to determine whether the combination of G-CSF/SCF induces angiogenesis in the central nervous system by promoting entry of endothelial precursors into the injured brain and causing them to proliferate there. We induced permanent middle cerebral artery occlusion in female mice that previously underwent sex-mismatched bone marrow transplantation from enhanced green fluorescent protein (EGFP)–expressing mice. G-CSF/SCF treatment reduced infarct volumes by more than 50% and resulted in a 1.5-fold increase in vessel formation in mice with stroke, a large percentage of which contain endothelial cells of bone marrow origin. Most cells entering the brain maintained their bone marrow identity and did not transdifferentiate into neural cells. G-CSF/SCF treatment also led to a 2-fold increase in the number of newborn cells in the ischemic hemisphere. These findings suggest that G-CSF/SCF treatment might help recovery through induction of bone marrow–derived angiogenesis, thus improving neuronal survival and functional outcome.

scholarly journals 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

2021 ◽  
Vol 8 ◽  
Author(s):  
Suning Ping ◽  
Xuecheng Qiu ◽  
Maria E. Gonzalez-Toledo ◽  
Xiaoyun Liu ◽  
Li-Ru Zhao
Keyword(s):  
Stem Cell ◽  
Mouse Model ◽  
Stem Cell Factor ◽  
Small Vessel Disease ◽  
Small Vessel ◽  
Repeated Treatment ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Neuron Loss ◽  
Stimulating Factor

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.

scholarly journals The Role of Stem Cell Factor and Granulocyte-Colony Stimulating Factor in Brain Repair during Chronic Stroke

2009 ◽  
Vol 29 (4) ◽  
pp. 759-770 ◽  
Author(s):  
Chun-Shu Piao ◽  
Maria E Gonzalez-Toledo ◽  
Yue-Qiang Xue ◽  
Wei-Ming Duan ◽  
Satoshi Terao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Stem Cell ◽  
Brain Imaging ◽  
Stem Cell Factor ◽  
Chronic Stroke ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Bone Marrow Derived Cells ◽  
Stimulating Factor

Chronic stroke is a highly important but under-investigated scientific problem in neurologic research. We have reported earlier that stem cell factor (SCF) in combination with granulocyte-colony stimulating factor (G-CSF) treatment during chronic stroke improves functional outcomes. Here we have determined the contribution of bone marrow-derived cells in angiogenesis and neurogenesis, which are enhanced by SCF + G-CSF treatment during chronic stroke. Using bone marrow tracking, flow cytometry, 2-photon live brain imaging, and immunohistochemistry, we observed that the levels of circulating bone marrow stem cells (BMSCs) (CD34+ /c-kit +) were significantly increased by SCF +G-CSF treatment. In addition, live brain imaging revealed that numerous bone marrow-derived cells migrate into the brain parenchyma in the treated mice. We also found that bone marrow-derived cells, bone marrow-derived endothelial cells, vascular density, and bone marrow-derived neurons were significantly augmented by SCF + G-CSF. It is interesting that, in addition to the increase in bone marrow-derived endothelial cells, the number of bone marrow-derived pericytes was reduced after SCF + G-CSF treatment during chronic stroke. These data suggest that SCF + G-CSF treatment can enhance repair of brain damage during chronic stroke by mobilizing BMSCs, and promoting the contribution of bone marrow-derived cells to angiogenesis and neurogenesis.

scholarly journals Cytokine-induced osteopoietic differentiation of transplanted marrow cells

Blood ◽  
2011 ◽  
Vol 118 (8) ◽  
pp. 2358-2361 ◽  
Author(s):  
Satoru Otsuru ◽  
Valeria Rasini ◽  
Rita Bussolari ◽  
Ted J. Hofmann ◽  
Massimo Dominici ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Hormone ◽  
Stem Cell ◽  
Stem Cell Factor ◽  
Cytokine Therapy ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Osteoprogenitor Cells ◽  
Stimulating Factor ◽  
Marrow Cells

Abstract Transplantation of whole bone marrow (BMT) leads to engraftment of both osteoprogenitor cells and hematopoietic cells; however, the robust osteopoietic chimerism seen early after BMT decreases with time. Using our established murine model, we demonstrate that a post-BMT regimen of either granulocyte-colony stimulating factor, growth hormone, parathyroid hormone, or stem cell factor each stimulates greater donor osteoblast chimerism at 4 months posttransplantation than saline-treated controls and approximates the robust osteopoietic chimerism seen early after BMT; however, only growth hormone led to significantly more donor-derived osteocytes than controls. Importantly, there were no adverse hematologic consequences of the different treatments. Our data demonstrate that these cytokines can stimulate the differentiation of transplanted donor marrow cells into the osteopoietic lineage after BMT. Post-BMT cytokine therapy may generate durable osteopoietic engraftment, which should lead to sustained clinical benefit and render BMT more applicable to bone disorders.

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

2015 ◽  
Vol 73 ◽  
pp. 189-203 ◽  
Author(s):  
Xiao-Yun Liu ◽  
Maria E. Gonzalez-Toledo ◽  
Austin Fagan ◽  
Wei-Ming Duan ◽  
Yanying Liu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mouse Model ◽  
Stem Cell Factor ◽  
Therapeutic Effects ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Stimulating Factor
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