Intravenously Delivered Allogeneic Mesenchymal Stem Cells Bidirectionally Regulate Inflammation and Induce Neurotrophic Effects in Distal Middle Cerebral Artery Occlusion Rats Within the First 7 Days After Stroke

Li, Xiaobo; Huang, Min; Zhao, Renchao; Zhao, Chunli; Liu, Yao; Zou, Haiqiang; Chen, Ling; Guan, Yunqian; Zhang, Y Alex

doi:10.1159/000489384

Cited by 47 publications

(35 citation statements)

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“…Grid walking test was used to measure motor coordination deficits after ischemic stroke for each group . The mice were placed on an elevated square grid with each grid cell being 1.5 × 1.5 cm 2 .…”

Section: Methodsmentioning

confidence: 99%

P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis

et al. 2020

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Introduction Clearance of damaged cells and debris is beneficial for the functional recovery after ischemic brain injury. However, the specific phagocytic receptor that mediates microglial phagocytosis after ischemic stroke is unknown. Aim To investigate whether P2Y6 receptor‐mediated microglial phagocytosis is beneficial for the debris clearance and functional recovery after ischemic stroke. Results The expression of the P2Y6 receptor in microglia increased within 3 days after transient middle cerebral artery occlusion. Inhibition of microglial phagocytosis by the selective inhibitor MRS2578 enlarged the brain atrophy and edema volume after ischemic stroke, subsequently aggravated neurological function as measured by modified neurological severity scores and Grid walking test. MRS2578 treatment had no effect on the expression of IL‐1α, IL‐1β, IL‐6, IL‐10, TNF‐α, TGF‐β, and MPO after ischemic stroke. Finally, we found that the expression of myosin light chain kinase decreased after microglial phagocytosis inhibition in the ischemic mouse brain, which suggested that myosin light chain kinase was involved in P2Y6 receptor‐mediated phagocytosis. Conclusion Our results indicate that P2Y6 receptor‐mediated microglial phagocytosis plays a beneficial role during the acute stage of ischemic stroke, which can be a therapeutic target for ischemic stroke.

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Section: Methodsmentioning

confidence: 99%

P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis

et al. 2020

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“…In brief, primary cultures of bone marrow stromal cells were obtained from donor young adult male rats, and BMSCs were isolated as previously described [ 15 , 19 ]. Animals were anesthetized with 3.5% isoflurane and then maintained with 1.0–2.0% isoflurane in N 2 O : O 2 (2 : 1).…”

Section: Methodsmentioning

confidence: 99%

“…By using immunostaining, we found that IGF-1 signals are mainly located in the infarct area. A minority of IGF-1 signals colocalize with NeuN+ neurons and CD68+-activated microglia in infarcts; nonetheless, quantitative analysis showed that these cells cannot account for all of the IGF-1-positive signals [ 15 ]. Other contributors in the brain and periphery (IGF-1 can cross the blood-brain barrier (BBB) [ 16 – 18 ]) to the increased IGF-1 signals in the brain warrant further investigation.…”

Section: Introductionmentioning

confidence: 99%

Peripheral Circulation and Astrocytes Contribute to the MSC-Mediated Increase in IGF-1 Levels in the Infarct Cortex in a dMCAO Rat Model

Guan

et al. 2020

Stem Cells International

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Background and Purpose. Previously, we found that insulin-like growth factor-1 (IGF-1) levels in the infarct cortex in the acute phase of distal middle cerebral artery occlusion (dMCAO) rats are increased by intravenous infusion of allogeneic mesenchymal stem/stromal cells (MSCs). CD68+ microglia and NeuN+ neurons are part, but not all, of the sources of IGF-1. The present study is aimed at exploring the respective contributions of brain endogenous Iba-1+ microglia, GFAP+ astrocytes, infiltrated neutrophils, lymphocytes and monocytes/macrophages, and peripheral circulation, to the increased IGF-1 level in the infarct cortex after MSC infusion. Materials and Methods. Ischemic brain injury was induced by dMCAO in Sprague-Dawley rats. The transplantation group received MSC infusion 1 h after dMCAO. Expression of IGF-1 in GFAP+ astrocytes, Iba-1+ microglia/macrophages, CD3+ lymphocytes, Ly6C+ monocytes/macrophages, and neutrophil elastase (NE)+ neutrophils was examined to determine the contribution of these cells to the increase of IGF-1. ELISA was performed to examine IGF-1 levels in blood plasma at days 2, 4, and 7 after ischemia onset. Results. In total, only 5-6% of Iba-1+ microglia were colabeled with IGF-1 in the infarct cortex, corpus callosum, and striatum at day 2 post-dMCAO. MSC transplantation did not lead to a higher proportion of Iba-1+ cells that coexpressed IGF-1. In the infarct cortex, all Iba-1+/IGF-1+ double-positive cells were also positive for CD68. In the infarct, corpus callosum, and striatum, the majority (50-80%) of GFAP+ cells were colabeled with ramified IGF-1 signals. The number of GFAP+/IGF-1+ cells was further increased following MSC treatment. In the infarct cortex, approximately 15% of IGF-1+ cells were double-positive for CD3. MSC treatment reduced the number of infiltrated CD3+/IGF-1+ cells by 70%. In the infarct, few Ly6C+ monocytes/macrophages or NE+ neutrophils expressed IGF-1, and MSC treatment did not induce a higher percentage of these cells that coexpressed IGF-1. The IGF-1 level in peripheral blood plasma was significantly higher in the MSC group than in the ischemia control group. Conclusion. The MSC-mediated increase in IGF-1 levels in the infarct cortex mainly derives from two sources, astrocytes in brain and blood plasma in periphery. Manipulating the IGF-1 level in the peripheral circulation may lead to a higher level of IGF-1 in brain, which could be conducive to recovery at the early stage of dMCAO.

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“…Grid walking test was used to measure motor coordination deficits after ischemic stroke for each group [30]. The mice were placed on an elevated square grid with each grid cell 1.5X1.5 cm 2 .…”

Section: Grid Walking Testmentioning

confidence: 99%

P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis

Wen

Shen

Huang

et al. 2019

Preprint

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Background Clearance of damaged cells is beneficial for the functional recovery after brain injury. Phagocytosis of tissue and cell debris is an important function of microglia during the development and pathological diseases. However, which specific phagocytic receptor mediates microglial phagocytosis after ischemic stroke is obscure. Methods ICR mice (n=59) underwent 90 minutes transient middle cerebral artery occlusion. P2Y6R, Iba1, GFAP and Tuj-1 double immunostainings were performed to determine P2Y6 receptor location. MRS2578 was injected into mice to inhibit P2Y6 receptor activity. Iba1 and TUNEL staining were performed to examine microglia phagocytosis. Modified neurological severity scores and Grid walking test were used to evaluate the neurological function after ischemic stoke. The expression of IL-1 α, IL-1 β, IL-6, IL-10, TNF-α, TGF-β and MPO was used to examine the inflammation response in the brain. Results The expression of P2Y6 receptor in microglia increased within three days after transient middle cerebral artery occlusion. Inhibition of microglial phagocytosis by the selective inhibitor MRS2578 enlarged the brain atrophy and edema volume after ischemic stroke, subsequently aggravated neurological function using modified neurological severity scores and Grid walking test. MRS2578 treatment had no effect on the expression of IL-1α, IL-1β, IL-6, IL-10, TNF-α, TGF-β and MPO after ischemic stroke, which suggested that it had no effect on the inflammation in the brain. Finally, we found that the expression of myosin light chain kinase decreased after microglial phagocytosis inhibition in ischemic mice, which suggested that myosin light chain kinase was involved in P2Y6 receptor mediated phagocytosis. Conclusion Our results indicated that the P2Y6 receptor mediated microglial phagocytosis played an important role during the acute stage of ischemic stroke, which was a potential target for ischemic stroke treatment.

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Intravenously Delivered Allogeneic Mesenchymal Stem Cells Bidirectionally Regulate Inflammation and Induce Neurotrophic Effects in Distal Middle Cerebral Artery Occlusion Rats Within the First 7 Days After Stroke

Cited by 47 publications

References 50 publications

P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis

P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis

Peripheral Circulation and Astrocytes Contribute to the MSC-Mediated Increase in IGF-1 Levels in the Infarct Cortex in a dMCAO Rat Model

P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis

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