Angiopoietin1/TIE2 and VEGF/FLK1 Induced by MSC Treatment Amplifies Angiogenesis and Vascular Stabilization after Stroke

Zacharek, Alex; Chen, Jieli; Cui, Xu; Li, Ang; Li, Yang; Roberts, Cynthia J.; Feng, Yifan; Gao, Qi; Chopp, Michael

doi:10.1038/sj.jcbfm.9600475

Cited by 252 publications

(214 citation statements)

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“…This capacity of MSCs may be of particular importance in facilitating EC migration into dense micro-organs such as islets. In addition, MSCs most likely contributed growth factors and extracellular matrix production that serve to encourage the stabilization and maturation of the EC sprouts (9). This effect of MSCs was evidenced by the increased sprout formation by EC-MSC islets in fibrin gels, where close interactions between EC sprouts and MSCs occurred to a high degree.…”

Section: Discussionmentioning

confidence: 97%

“…MSCs have also been shown to upregulate the expression of angiopoietin and vascular endothelial growth factor (VEGF) in ECs, contributing to an increase in angiogenesis and stabilization of the vasculature (9). Moreover, MSCs have been shown to possess important immune-modulating properties (10), and they do not trigger adaptive immune reactions, which could make them ideal in islet transplantation setting (11,12).…”

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confidence: 99%

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Formation of Composite Endothelial Cell–Mesenchymal Stem Cell Islets

et al. 2008

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OBJECTIVE-Mesenchymal stem cells (MSCs) contribute to endothelial cell (EC) migration by producing proteases, thereby paving the way into the tissues for ECs. MSCs were added to our previously described composite EC islets as a potential means to improve their capacity for islet angiogenesis.RESEARCH DESIGN AND METHODS-Human islets were coated with primary human bone marrow-derived MSCs and dermal microvascular ECs. The capacity of ECs, with or without MSCs, to adhere to and grow into human islets was analyzed. The survival and functionality of these composite islets were evaluated in a dynamic perifusion assay, and their capacity for angiogenesis in vitro was assessed in a three-dimensional fibrin gel assay.RESULTS-ECs proliferated after culture in MSC-conditioned medium, and MSCs improved the EC coverage threefold compared with EC islets alone. Islet survival in vitro and the functionality of the composite islets after culture were equal to those of control islets. The EC-MSC islets showed a twofold increase in total sprout formation compared with EC islets, and vascular sprouts emanating from the EC-MSC-islet surface showed migration of ECs into the islets and also into the surrounding matrix, either alone or in concert with MSCs. T he islets of Langerhans are micro-organs, with afferent and efferent blood vessels connecting the capillary network of the islets to the circulation system (1). Intra-islet endothelial cells (ECs) are fenestrated, and the density of the capillary network in the islets is ϳ10 times higher than that of the surrounding exocrine tissue (2,3). During the process of islet isolation before transplantation, the ECs in the islets lose their external vascular support; this situation contributes to their dedifferentiation, apoptosis, and necrosis during subsequent in vitro culture (4). CONCLUSIONS-ECThe formation of new capillaries during revascularization is a complex process that involves digestion of the vascular wall by proteases and the migration, proliferation, and differentiation of ECs (5). When blood vessels are assembled, ECs produce platelet-derived growth factor, which attracts supportive cells, including mesenchymal stem cells (MSCs) that can differentiate into pericytes (6).We hypothesized that adding MSCs to our previously described composite EC islets (7) might improve the adherence of the ECs to the islets and subsequent vascularization because MSCs contribute to EC migration by producing proteases, thereby paving the way into the surrounding tissue for the immature EC sprouts (8). MSCs have also been shown to upregulate the expression of angiopoietin and vascular endothelial growth factor (VEGF) in ECs, contributing to an increase in angiogenesis and stabilization of the vasculature (9). Moreover, MSCs have been shown to possess important immune-modulating properties (10), and they do not trigger adaptive immune reactions, which could make them ideal in islet transplantation setting (11,12).The present study describes a gentle and reproducible technique for forming EC-MSC i...

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Section: Discussionmentioning

confidence: 97%

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confidence: 99%

Formation of Composite Endothelial Cell–Mesenchymal Stem Cell Islets

et al. 2008

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“…Therefore, it is important in the clinical treatment of cerebral ischemia to improve or restore cerebral blood flow in early cerebral ischemia. Many evidences have shown that a higher microvessel density means a significantly better prognosis for patients with stroke, and angiogenesis can improve blood perfusion in brain tissue surrounding the ischemic area in rats and promote neurological function recovery after ischemia (Zacharek et al., 2007). Meanwhile, some studies found that cerebral ischemia can cause auto‐angiogenesis in the ischemic region (Beck & Plate, 2009).…”

Section: Discussionmentioning

confidence: 99%

Effects of treadmill exercise on cerebral angiogenesis and MT1‐MMP expression after cerebral ischemia in rats

et al. 2018

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IntroductionDespite the increased understanding of treadmill training on angiogenesis of stroke patients, its mechanism is not clearly known. The metalloproteinase membrane type 1‐metalloprotease (MT1‐MMP) promotes the regeneration of the peripheral vessels but seldom research on the regeneration of cerebral blood vessels. This study was designed to investigate the effects of treadmill exercise on angiogenesis and MT1‐MMP expression after cerebral ischemia in rats.MethodsThe adult male Sprague Dawley(SD) rats were randomly divided into three groups: sham operation group, the middle cerebral artery occlusion group(MCAO) and middle cerebral artery occlusion group(MCAO)+exercise group. In 4d, 7d or 14d after MCAO, respectively, the rats’ neurological function was evaluated by the modified neurologic severity scores (mNSS); the microvessel numbers in areas surrounding cerebral ischemia were counted with Microvessel Density(MVD)analysis; the levels of MT1‐MMP and reversion‐inducing cysteine‐rich protein with Kazalmotifs (RECK) were detected by Western‐blot and immunohistochemical method.ResultsCompared with MCAO group, the number of capillaries and the level of MT1‐MMP expression around the area of cerebral ischemia were significantly increased in each exercise group (p < 0.05), while the level of RECK expression and the scores of mNSS in each exercise group were significantly decreased (p < 0.05).ConclusionThis study suggested that treadmill exercise training can significantly promote angiogenesis and improve neurological function after cerebral ischemia. Its mechanism may be related to the upgraduation of the MT1‐MMP expression in brain microvessels surrounding area of the ischemic rat.

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“…We first referred to two classic endothelial angiogenesis-related pathways both in vitro and in vivo: VEGF signaling [6,7,22] and angiopoietin/TIE2 signaling [34,35]. However, the RNA-seq results did not show significant elevation of upstream ligands or receptors for these pathways in co-HUVECs within 24 h. Alternatively, unbiased analysis demonstrated that a large proportion of experimentally validated NF-kB target genes (mainly based on www.bu.edu/NF-kB/gene-resources/target genes) were upregulated upon coculture for 12 and 24 h in both co-HUVECs and co-HMSCs (Fig.…”

Section: Rna-seq Revealed Differential Gene Expression Profiles and Amentioning

confidence: 99%

Transcriptional Profiling Reveals Crosstalk Between Mesenchymal Stem Cells and Endothelial Cells Promoting Prevascularization by Reciprocal Mechanisms

LiJunxiang

MaYing

TengRuifang

et al. 2015

Stem Cells and Development

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Mesenchymal stem cells (MSCs) show great promise in blood vessel restoration and vascularization enhancement in many therapeutic situations. Typically, the co-implantation of MSCs with vascular endothelial cells (ECs) is effective for the induction of functional vascularization in vivo, indicating its potential applications in regenerative medicine. The effects of MSCs-ECs-induced vascularization can be modeled in vitro, providing simplified models for understanding their underlying communication. In this article, a contact coculture model in vitro and an RNA-seq approach were employed to reveal the active crosstalk between MSCs and ECs within a short time period at both morphological and transcriptional levels. The RNA-seq results suggested that angiogenic genes were significantly induced upon coculture, and this prevascularization commitment might require the NF-kB signaling. NF-kB blocking and interleukin (IL) neutralization experiments demonstrated that MSCs potentially secreted IL factors including IL1b and IL6 to modulate NF-kB signaling and downstream chemokines during coculture. Conversely, RNA-seq results indicated that the MSCs were regulated by the coculture environment to a smooth muscle commitment within this short period, which largely induced myocardin, the myogenic co-transcriptional factor. These findings demonstrate the mutual molecular mechanism of MSCs-ECs-induced prevascularization commitment in a quick response.

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Angiopoietin1/TIE2 and VEGF/FLK1 Induced by MSC Treatment Amplifies Angiogenesis and Vascular Stabilization after Stroke

Cited by 252 publications

References 35 publications

Formation of Composite Endothelial Cell–Mesenchymal Stem Cell Islets

Formation of Composite Endothelial Cell–Mesenchymal Stem Cell Islets

Effects of treadmill exercise on cerebral angiogenesis and MT1‐MMP expression after cerebral ischemia in rats

Transcriptional Profiling Reveals Crosstalk Between Mesenchymal Stem Cells and Endothelial Cells Promoting Prevascularization by Reciprocal Mechanisms

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