Impaired Vascular Remodeling after Endothelial Progenitor Cell Transplantation in MMP9-Deficient Mice Suffering Cortical Cerebral Ischemia

Morancho, Anna; Ma, Feifei; Barceló, Verónica; Giralt, Dolors; Montaner, Joan; Rosell, Anna

doi:10.1038/jcbfm.2015.180

Cited by 33 publications

(22 citation statements)

References 17 publications

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“…40 Our results indicated that more EPCs were mobilized and migrated to the ischemic injury site after MMP-9-triggered glial scar degradation, and MMP-9 was essential for ischemiainduced neovascularization by either modulating bone-marrowderived EPCs or activating the VEGF signaling pathway. 39,41,42 How MMP-9 affected VEGFR2 and how EPCs regulated the formation of the vascular network after MMP-9 treatment in ischemic stroke need further investigation. Furthermore, EPC-secreted angiogenic cytokines, such as VEGF, hepatocyte growth factor (HGF), granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor, also played important roles.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Response Element-Regulated MMP-9 Promotes Neurological Recovery via Glial Scar Degradation and Angiogenesis in Delayed Stroke

Cai

Jiang

et al. 2017

Molecular Therapy

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Matrix metalloproteinase 9 (MMP-9) plays a beneficial role in the delayed phase of middle cerebral artery occlusion (MCAO). However, the mechanism is obscure. Here, we constructed hypoxia response element (HRE)-regulated MMP-9 to explore its effect on glial scars and neurogenesis in delayed ischemic stroke. Adult male Institute of Cancer Research (ICR) mice underwent MCAO and received a stereotactic injection of lentivirus carrying HRE-MMP-9 or normal saline (NS)/lentivirus-GFP 7 days after ischemia. We found that HRE-MMP-9 improved neurological outcomes, reduced ischemia-induced brain atrophy, and degraded glial scars (p < 0.05). Furthermore, HRE-MMP-9 increased the number of microvessels in the peri-infarct area (p < 0.001), which may have been due to the accumulation of endogenous endothelial progenitor cells (EPCs) in the peri-infarct area after glial scar degradation. Finally, HRE-MMP-9 increased the number of bromodeoxyuridine-positive (BrdU)/NeuN cells and the expression of PSD-95 in the peri-infarct area (p < 0.01). These changes could be blocked by vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor SU5416 and MMP-9 inhibitor 2-[[(4-phenoxyphenyl)sulfonyl]methyl]-thiirane (SB-3CT). Our results provided a novel mechanism by which glial scar degradation and vascular endothelial growth factor (VEGF)/VEGFR2-dependent angiogenesis may be key procedures for neurological recovery in delayed ischemic stroke after HRE-MMP-9 treatment. Therefore, HRE-MMP-9 overexpression in the delayed ischemic brain is a promising approach for neurological recovery.

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Section: Discussionmentioning

confidence: 99%

Hypoxia Response Element-Regulated MMP-9 Promotes Neurological Recovery via Glial Scar Degradation and Angiogenesis in Delayed Stroke

Cai

Jiang

et al. 2017

Molecular Therapy

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“…EPCs are highly migratory and can home to target areas to regulate angiogenesis and vasculogenesis for tissue homeostasis or repair. In the context of central nervous system (CNS) injury and disease, EPCs may contribute to neurovascular recovery after stroke . However, the underlying mechanisms remain to be fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Protective Effects of Endothelial Progenitor Cell-Derived Extracellular Mitochondria in Brain Endothelium

et al. 2018

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Endothelial progenitor cells (EPCs) have been pursued as a potential cellular therapy for stroke and central nervous system injury. However, their underlying mechanisms remain to be fully defined. Recent experimental studies suggest that mitochondria may be released and transferred between cells. In this proof-of-concept study, we asked whether beneficial effects of EPCs may partly involve a mitochondrial phenomenon as well. First, EPC-derived conditioned medium was collected and divided into supernatant and particle fractions after centrifugation. Electron microscopy, Western blots, and flow cytometry showed that EPCs were able to release mitochondria. ATP and oxygen consumption assays suggested that these extracellular mitochondria may still be functionally viable. Confocal microscopy confirmed that EPC-derived extracellular mitochondria can be incorporated into normal brain endothelial cells. Adding EPC particles to brain endothelial cells promoted angiogenesis and decreased the permeability of brain endothelial cells. Next, we asked whether EPC-derived mitochondria may be protective. As expected, oxygen-glucose deprivation (OGD) increased brain endothelial permeability. Adding EPC-derived mitochondria particles to the damaged brain endothelium increased levels of mitochondrial protein TOM40, mitochondrial DNA copy number, and intracellular ATP. Along with these indirect markers of mitochondrial transfer, endothelial tightness was also restored after OGD. Taken together, these findings suggest that EPCs may support brain endothelial energetics, barrier integrity, and angiogenic function partly through extracellular mitochondrial transfer. Stem Cells 2018;36:1404-1410.

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“…Mesenchymal stem cells (MSCs) are multipotent stem cells capable of self‐renew, differentiating, and participating in angiogenesis. Both MSCs and EPCs take part in vascularization and tissue repair and have been widely employed for cell‐based therapy in both preclinical studies and clinical trials .…”

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confidence: 99%

Coculture of endothelial progenitor cells and mesenchymal stem cells enhanced their proliferation and angiogenesis through PDGF and Notch signaling

et al. 2017

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The beneficial effects of combined use of mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) on tissue repair and regeneration after injury have been demonstrated, but the underlying mechanism remains incompletely understood. This study aimed to investigate the effects of direct contact coculture of human bone marrow‐derived EPCs (hEPCs)/human bone marrow‐derived MSCs (hMSCs) on their proliferation and angiogenic capacities and the underlying mechanism. hEPCs and hMSCs were cocultured in a 2D mixed monolayer or a 3D transwell membrane cell‐to‐cell coculture system. Cell proliferation was determined by Cell Counting Kit‐8. Angiogenic capacity was evaluated by in vitro angiogenesis assay. Platelet‐derived growth factor‐BB (PDGF‐BB), PDGF receptor neutralizing antibody (AB‐PDGFR), and DAPT (a γ‐secretase inhibitor) were used to investigate PDGF and Notch signaling. Cell proliferation was significantly enhanced by hEPCs/hMSCs 3D‐coculture and PDGF‐BB treatment, but inhibited by AB‐PDGFR. Expression of cyclin D1, PDGFR, Notch1, and Hes1 was markedly enhanced by PDGF‐BB but inhibited by DAPT. In vitro angiogenesis assay showed that hEPCs/hMSCs coculture and PDGF‐BB significantly enhanced angiogenic capacity, whereas AB‐PDGFR significantly reduced the angiogenic capacity. PDGF‐BB increased the expression of kinase insert domain receptor (KDR, an endothelial marker) and activated Notch1 signaling in cocultured cells, while DAPT attenuated the promoting effect of PDGF‐BB on KDR expression of hEPCs/hMSCs coculture. hEPCs/hMSCs coculture enhanced their proliferation and angiogenic capacities. PDGF and Notch signaling pathways participated in the promoting effects of hEPCs/hMSCs coculture, and there was crosstalk between these two signaling pathways. Our findings should aid understanding of the mechanism of beneficial effects of hEPCs/hMSCs coculture.

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Impaired Vascular Remodeling after Endothelial Progenitor Cell Transplantation in MMP9-Deficient Mice Suffering Cortical Cerebral Ischemia

Cited by 33 publications

References 17 publications

Hypoxia Response Element-Regulated MMP-9 Promotes Neurological Recovery via Glial Scar Degradation and Angiogenesis in Delayed Stroke

Hypoxia Response Element-Regulated MMP-9 Promotes Neurological Recovery via Glial Scar Degradation and Angiogenesis in Delayed Stroke

Protective Effects of Endothelial Progenitor Cell-Derived Extracellular Mitochondria in Brain Endothelium

Coculture of endothelial progenitor cells and mesenchymal stem cells enhanced their proliferation and angiogenesis through PDGF and Notch signaling

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