Cerebral ischemia induces angiogenesis in the peri-infarct regions via Notch1 signaling activation

Ren, Chang­hong; Yu, Yao; Han, Rongrong; Huang, Qiuchen; Li, Haiyan; Wang, Brian; Li, Sijie; Li, Ming; Mao, Ying; Mao, XiaoOu; Xie, Lin; Zhou, Lei; Hu, Jiangnan; Ji, Xunming; Jin, Kunlin

doi:10.1016/j.expneurol.2018.02.013

Cited by 37 publications

(20 citation statements)

References 36 publications

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“…The permanent distal middle cerebral artery occlusion (pMCAO) model was used to create permanent focal ischemia, as previously described (Ren et al, 2018). Briefly, Sprague-Dawley rats were anesthetized and incised between their left eye socket and tragus.…”

Section: Stroke Model and Exosome Injectionmentioning

confidence: 99%

Melatonin Enhances the Therapeutic Effect of Plasma Exosomes Against Cerebral Ischemia-Induced Pyroptosis Through the TLR4/NF-κB Pathway

Wang

Zhang

et al. 2020

Front. Neurosci.

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Introduction: Ischemic stroke-induced inflammation and inflammasome-dependent pyroptotic neural death cause serious neurological injury. Nano-sized plasma exosomes have exhibited therapeutic potential against ischemia and reperfusion injury by ameliorating inflammation. To enhance its therapeutic potential in patients with ischemic injury, we isolated exosomes from melatonin-treated rat plasma and assessed the neurological protective effect in a rat model of focal cerebral ischemia. Methods: Basal plasma exosomes and melatonin-treated plasma exosomes were isolated and intravenously injected into a rat model of focal cerebral ischemia. Neurological recovery was evaluated by determining the modified neurological severity score (mNSS), infarct volume, and brain water content. Pyroptosis in the ischemic cortex was detected through dUTP nick-end labeling (TUNEL) assay, lactate dehydrogenase (LDH) release, and gasdermin D (GSDMD) cleavage. NLRP3 inflammasome assembly and global inflammatory cytokine secretion were detected by enzyme-linked immunosorbent assay (ELISA) and Western blot assay. In immunized Sprague-Dawley rats, microglia pyroptosis was determined through a positive percentage of IBA1 + and caspase-1 (p20) + cells. Finally, the microRNA (miRNA) profiles in melatonin-treated plasma exosomes were analyzed by exosome miRNA microarray analysis. Results: Melatonin treatment enhanced plasma exosome therapeutic effects against ischemia-induced inflammatory responses and inflammasome-mediated pyroptosis. In addition, we confirmed that ischemic stroke-induced pyroptotic cell death occurred in the microglia and neuron, while the administration of melatonin-treated exosomes further effectively decreased the infarct volume and improved recovery of function via regulation of the TLR4/NF-κB signaling pathway. Finally, the altered miRNA profiles in the melatonin-treated plasma exosomes demonstrated the regulatory mechanisms involved in neurological recovery after ischemic injury.

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Section: Stroke Model and Exosome Injectionmentioning

confidence: 99%

Melatonin Enhances the Therapeutic Effect of Plasma Exosomes Against Cerebral Ischemia-Induced Pyroptosis Through the TLR4/NF-κB Pathway

Wang

Zhang

et al. 2020

Front. Neurosci.

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“…The massive death of donor cells in the contusion area during the acute phase resulting from increased free radicals and inflammatory responses immensely lowers the efficacy of the cell-based treatment. In order to improve the effect of stem cell-based therapy, various strategies have been adopted to develop and optimize the protocols to enhance donor stem cell survival post-transplantation, with special attention being paid to preconditioning approaches [44, 45]. Presently, several preconditioning triggers are being tested in stem cell-based therapy and have shown to increase the tolerance of transplanted cells to multiple injurious insults [46, 47].…”

Section: Discussionmentioning

confidence: 99%

“…The neuroprotective microenvironment attributed to the pretreatment with MDL28170, 30 min after TBI and before BMSC transplantation, may be of benefit to enhance the survivability of transplanted cells. Calpain inhibitors have been reported to inhibit both apoptosis and necrosis [55, 56], have neuroprotective effects in numerous rodent neurotrauma models, including TBI, spinal cord injury [23], and focal cerebral ischemia [45, 56, 57]. In fact, treatment with MDL28170 rescued transplanted BMSCs in the injured spinal cord by modulating ER stress-induced apoptosis [58].…”

Section: Discussionmentioning

confidence: 99%

Calpain inhibitor MDL28170 improves the transplantation-mediated therapeutic effect of bone marrow-derived mesenchymal stem cells following traumatic brain injury

Hu¹,

Chen²,

Huang³

et al. 2019

Stem Cell Res Ther

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BackgroundStudies have shown that transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) protects against brain damage. However, the low survival number of transplanted BMSCs remains a pertinent challenge and can be attributed to the unfavorable microenvironment of the injured brain. It is well known that calpain activation plays a critical role in traumatic brain injury (TBI)-mediated inflammation and cell death; previous studies showed that inhibiting calpain activation is neuroprotective after TBI. Thus, we investigated whether preconditioning with the calpain inhibitor, MDL28170, could enhance the survival of BMSCs transplanted at 24 h post TBI to improve neurological function.MethodsTBI rat model was induced by the weight-drop method, using the gravitational forces of a free falling weight to produce a focal brain injury. MDL28170 was injected intracranially at the lesion site at 30 min post TBI, and the secretion levels of neuroinflammatory factors were assessed 24 h later. BMSCs labeled with green fluorescent protein (GFP) were locally administrated into the lesion site of TBI rat brains at 24 h post TBI. Immunofluorescence and histopathology were performed to evaluate the BMSC survival and the TBI lesion volume. Modified neurological severity scores were chosen to evaluate the functional recovery. The potential mechanisms by which MDL28170 is involved in the regulation of inflammation signaling pathway and cell apoptosis were determined by western blot and immunofluorescence staining.ResultsOverall, we found that a single dose of MDL28170 at acute phase of TBI improved the microenvironment by inhibiting the inflammation, facilitated the survival of grafted GFP-BMSCs, and reduced the grafted cell apoptosis, leading to the reduction of lesion cavity. Furthermore, a significant neurological function improvement was observed when BMSCs were transplanted into a MDL28170-preconditioned TBI brains compared with the one without MDL28170-precondition group.ConclusionsTaken together, our data suggest that MDL28170 improves BMSC transplantation microenvironment and enhances the neurological function restoration after TBI via increased survival rate of BMSCs. We suggest that the calpain inhibitor, MDL28170, could be pursued as a new combination therapeutic strategy to advance the effects of transplanted BMSCs in cell-based regenerative medicine.Electronic supplementary materialThe online version of this article (10.1186/s13287-019-1210-4) contains supplementary material, which is available to authorized users.

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“…Then, NICD translocates to the nucleus to regulate gene transcription, thereby influencing the proliferation and differentiation of cells [45]. Notch1/NICD is involved in the angiogenesis of ischemic tissue and favours stem cell differentiation into cardiomyocytes [46–48]. In this study, CX-CS upregulated Notch and NICD expression and no longer increased the NICD level after Notch γ secretase was inhibited, which suggested that Notch1/NICD signalling might play an important role in the CX-CS-mediated promotion of angiogenesis in ischemic myocardium.…”

Section: Discussionmentioning

confidence: 99%

Combination ofLigusticum ChuanxiongandRadix PaeoniaPromotes Angiogenesis in Ischemic Myocardium through Notch Signalling and Mobilization of Stem Cells

Shi

Zhao

Yuan

et al. 2019

Evidence-Based Complementary and Alternative Medicine

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Objective. To study the cardioprotective mechanism by which the combination of Chuanxiong (CX) and Chishao (CS) promotes angiogenesis. Methods. Myocardial infarction (MI) mouse models were induced by ligation of the left anterior descending coronary artery. The effects on cardiac function were evaluated in the perindopril tert-butylamine group (PB group) (3 mg/kg/d), CX group (55 mg/kg/d), CS group (55 mg/kg/d), and CX and CS combination (CX-CS) group (27.5 mg/kg/d CX plus 27.5 mg/kg/d CS). RO4929097, an inhibitor of Notch γ secretase, was used (10 mg/kg/d) to explore the role of Notch signalling in the CX-CS-induced promotion of angiogenesis in the myocardial infarcted border zone (IBZ). The left ventricular ejection fraction (LVEF) and percentage of MI area were evaluated with animal ultrasound and Masson staining. The average optical densities (AODs) of CD31 and vWF in the myocardial IBZ were detected by immunofluorescence. Angiogenesis-related proteins including hypoxia-inducible factor 1-alpha (HIF-1α), fibroblast growth factor receptor 1 (FGFR-1), Notch1 and Notch intracellular domain (NICD), and stem cell mobilization-related proteins including stromal cell-derived factor 1 (SDF-1), C-X-C chemokine receptor type 4 (CXCR-4), and cardiotrophin1 were detected by western blot analysis. Results. Compared with the model group, the CX-CS and PB groups both showed markedly improved LVEF and decreased percentage of MI area after 21 days of treatment. Although the CX group and CS group showed increased LVEF and decreased MI areas compared with the model group, the difference was not significant. The AOD of CD31 in the IBZ in both the model and the CX-CS-I group was markedly reduced compared with that in the sham group. CX-CS significantly increased the CD31 AOD in the IBZ and decreased the AODs of CD31 and vWF in the infarct zone compared with those in the model group. The expression of HIF-1α in both the model group and the CX-CS group was higher than that in the sham group. Compared with the model group, the expression of FGFR-1, SDF-1, cardiotrophin1, Notch1, and NICD was increased in the CX-CS group. Notch1 and NICD expression in the CX-CS-I group was reduced compared with that in the CX-CS group. Conclusions. The combination of CX and CS protected cardiomyocytes in the IBZ better than CX or CS alone. The mechanism by which CX-CS protects ischemic myocardium may be related to the proangiogenesis effect of CX-CS exerted through Notch signalling and the mobilization of stem cells to the IBZ.

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Cerebral ischemia induces angiogenesis in the peri-infarct regions via Notch1 signaling activation

Cited by 37 publications

References 36 publications

Melatonin Enhances the Therapeutic Effect of Plasma Exosomes Against Cerebral Ischemia-Induced Pyroptosis Through the TLR4/NF-κB Pathway

Melatonin Enhances the Therapeutic Effect of Plasma Exosomes Against Cerebral Ischemia-Induced Pyroptosis Through the TLR4/NF-κB Pathway

Calpain inhibitor MDL28170 improves the transplantation-mediated therapeutic effect of bone marrow-derived mesenchymal stem cells following traumatic brain injury

Combination ofLigusticum ChuanxiongandRadix PaeoniaPromotes Angiogenesis in Ischemic Myocardium through Notch Signalling and Mobilization of Stem Cells

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