Increased CD68/TGFβ Co-expressing Microglia/ Macrophages after Transient Middle Cerebral Artery Occlusion in Rhesus Monkeys

Yeo, Hyeon-Gu; Hong, Jung Joo; Lee, Youngjeon; Yi, Kyung Sik; Jeon, Chang‐Yeop; Park, Junghyung; Won, Jinyoung; Seo, Ji Hun; Ahn, Yujin; Kim, Keon-Woo; Baek, Seung Ho; Hwang, Eunha; Kim, Green; Jin, Yeung Bae; Jeong, Kang-Jin; Koo, Bon‐Sang; Kang, Philyong; Lim, Kyung Seob; Kim, Sun-Uk; Huh, Jae‐Won; Kim, Younghyun; Son, Yeonghoon; Kim, Jisu; Choi, Chi-Hoon; Cha, Sang-Hoon; Lee, Sang-Rae

doi:10.5607/en.2019.28.4.458

Cited by 26 publications

(22 citation statements)

References 60 publications

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“…The impact of aging on the expression of TGF-β after stroke remains understudied. Microglia and monocyte-derived macrophages are thought to be major cellular sources of TGF-β within the brain after stroke (Yeo et al 2019). Previous studies have shown that TGF-β expression increases in the brain (Krupinski et al 1996) and blood (Jiang et al 2017) after stroke, leading to increased Smad signaling and reactive gliosis, which is further increased by aging (Doyle et al 2010;Cekanaviciute et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Transforming growth factor-β promotes basement membrane fibrosis, alters perivascular cerebrospinal fluid distribution, and worsens neurological recovery in the aged brain after stroke

et al. 2019

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Aging and stroke alter the composition of the basement membrane and reduce the perivascular distribution of cerebrospinal fluid and solutes, which may contribute to poor functional recovery in elderly patients. Following stroke, TGF-β induces astrocyte activation and subsequent glial scar development. This is dysregulated with aging and could lead to chronic, detrimental changes within the basement membrane. We hypothesized that TGF-β induces basement membrane fibrosis after stroke, leading to impaired perivascular CSF distribution and poor functional recovery in aged animals. We found that CSF entered the aged brain along perivascular tracts; this process was reduced by experimental stroke and was rescued by TGF-β receptor inhibition. Brain fibronectin levels increased with experimental stroke, which was reversed with inhibitor treatment. Exogenous TGF-β stimulation increased fibronectin expression, both in vivo and in primary cultured astrocytes. Oxygen-glucose deprivation of cultured astrocytes induced multiple changes in genes related to astrocyte activation and extracellular matrix

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Section: Discussionmentioning

confidence: 99%

Transforming growth factor-β promotes basement membrane fibrosis, alters perivascular cerebrospinal fluid distribution, and worsens neurological recovery in the aged brain after stroke

et al. 2019

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“…The transient endovascular MCAO technique was applied as in our previous study [ 24 , 25 ]. An endovascular occlude was advanced over micro-guidewire (Synchro 14, Boston Scientific, Fremont, CA) and wedged in the distal M1 or superior M2 division branch of the right MCA under double fluoroscopic roadmap images.…”

Section: Methodsmentioning

confidence: 99%

Assessment of Hand Motor Function in a Non-human Primate Model of Ischemic Stroke

Won

Choi

et al. 2020

Exp Neurobiol

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Ischemic stroke results from arterial occlusion and can cause irreversible brain injury. A non-human primate (NHP) model of ischemic stroke was previously developed to investigate its pathophysiology and for efficacy testing of therapeutic candidates; however, fine motor impairment remains to be well-characterized. We evaluated hand motor function in a cynomolgus monkey model of ischemic stroke. Endovascular transient middle cerebral artery occlusion (MCAO) with an angiographic microcatheter induced cerebral infarction. In vivo magnetic resonance imaging mapped and measured the ischemia-induced infarct lesion. In vivo diffusion tensor imaging (DTI) of the stroke lesion to assess the neuroplastic changes and fiber tractography demonstrated three-dimensional patterns in the corticospinal tract 12 weeks after MCAO. The hand dexterity task (HDT) was used to evaluate fine motor movement of upper extremity digits. The HDT was modified for a home cage-based training system, instead of conventional chair restraint training. The lesion was localized in the middle cerebral artery territory, including the sensorimotor cortex. Maximum infarct volume was exhibited over the first week after MCAO, which progressively inhibited ischemic core expansion, manifested by enhanced functional recovery of the affected hand over 12 weeks after MCAO. The total performance time decreased with increasing success rate for both hands on the HDT. Compensatory strategies and retrieval failure improved in the chronic phase after stroke. Our findings demonstrate the recovery of fine motor skill after stroke, and outline the behavioral characteristics and features of functional disorder of NHP stroke model, providing a basis for assessing hand motor function after stroke.

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“…[31][32][33][34] In our study, we found IBA1-positive microglia and CD68 and IBA1 double-positive cells increased in thalamus and cortex after irradiation. CD68 was recognized as microglial phagocytosis marker, 35,36 and increased microglia activity and neuroinflammation may contribute to gamma ray-induced brain lesion. 37 Indeed, several proinflammatory cytokines, such as IL-1β, IL-6, and TNF-α, appear to be involved in the brain's response to irradiation.…”

Section: F I G U R Ementioning

confidence: 99%

Gamma ray‐induced glial activation and neuronal loss occur before the delayed onset of brain necrosis

Wang

et al. 2020

FASEB j.

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Radiotherapy is one of the most effective treatments for head and neck tumors. However, delayed radiation‐induced brain necrosis (RN) remains a serious issue due to the lack of satisfying prevention and effective treatment. The pathological role of radiation in the delayed onset of brain necrosis is still largely unknown, and the traditional animal model of whole brain irradiation, although being widely used, does not produce reliable and localized brain necrosis mimicking clinical features of RN. In this study, we demonstrated a successful RN mouse model using optimized gamma knife irradiation in male C57BL/6 mice. On the premise that brain necrosis started to appear at 6 weeks postirradiation in our RN model, as confirmed by both MRI and histopathological examinations, we systematically examined different time points before the onset of RN for the histopathological changes and biochemical indicators. Our initial results demonstrated that in the ipsilateral hemisphere of the irradiated brains, a significant decrease in neuronal numbers that occurred at 4 weeks and a sustained increase in TNF‐α, iNOS, and other inflammatory cytokines beginning at 1‐week postirradiation. Changes of cell morphology and cell numbers of both microglia and astrocytes occurred as early as 1‐week postirradiation, and intervention by bevacizumab administration resulted in reduced microglia activation and reduction of radiation‐induced lesion volume, indicating that chronic glial activation may result in subsequent elevation of inflammatory factors, which led to the delayed onset of neuronal loss and brain necrosis. Since C57BL/6 is the most widely used strain of genetic engineered mouse model, our data provide an invaluable platform for the mechanistic study of RN pathogenesis, identification of potential imaging and biological biomarkers, and the development of therapeutic treatment for the disease.

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Increased CD68/TGFβ Co-expressing Microglia/ Macrophages after Transient Middle Cerebral Artery Occlusion in Rhesus Monkeys

Cited by 26 publications

References 60 publications

Transforming growth factor-β promotes basement membrane fibrosis, alters perivascular cerebrospinal fluid distribution, and worsens neurological recovery in the aged brain after stroke

Transforming growth factor-β promotes basement membrane fibrosis, alters perivascular cerebrospinal fluid distribution, and worsens neurological recovery in the aged brain after stroke

Assessment of Hand Motor Function in a Non-human Primate Model of Ischemic Stroke

Gamma ray‐induced glial activation and neuronal loss occur before the delayed onset of brain necrosis

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