Kings College London Bhf Center

United Kingdom

Kings College London Bhf Center

United Kingdom
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Gu W.,Kings College London Bhf Center | Hong X.,Kings College London Bhf Center | Potter C.,Kings College London Bhf Center | Qu A.,Capital Medical University | Xu Q.,Kings College London Bhf Center
Microcirculation | Year: 2017

In recent years, MSCs have emerged as a promising therapeutic cell type in regenerative medicine. They hold great promise for treating cardiovascular diseases, such as myocardial infarction and limb ischemia. MSCs may be utilized in both cell-based therapy and vascular graft engineering to restore vascular function, thereby providing therapeutic benefits to patients. The efficacy of MSCs lies in their multipotent differentiation ability toward vascular smooth muscle cells, endothelial cells and other cell types, as well as their capacity to secrete various trophic factors, which are potent in promoting angiogenesis, inhibiting apoptosis and modulating immunoreaction. Increasing our understanding of the mechanisms of MSC involvement in vascular regeneration will be beneficial in boosting present therapeutic approaches and developing novel ones to treat cardiovascular diseases. In this review, we aim to summarize current progress in characterizing the in vivo identity of MSCs, to discuss mechanisms involved in cell-based therapy utilizing MSCs, and to explore current and future strategies for vascular regeneration. © 2016 John Wiley & Sons Ltd


Yu B.,Kings College London Bhf Center
Circulation | Year: 2017

BACKGROUND—: Dickkopf-related protein (DKK) 3 is a secreted protein that is involved in the regulation of cardiac remodeling and vascular smooth muscle cell differentiation, but little is known about its role in atherosclerosis. METHODS—: We tested the hypothesis that DKK3 is atheroprotective using both epidemiological and experimental approaches. Blood DKK3 levels were measured in the Bruneck Study in 2000 (n=684) and then in 2005 (n=574). DKK3-deficient mice were crossed to ApoE mice to evaluate atherosclerosis development and vessel injury-induced neointimal formation. Endothelial cell migration and the underlying mechanisms were studied using in vitro cell culture models. RESULTS—: In the prospective population-based Bruneck Study, the level of plasma DKK3 was inversely related to carotid artery intima-media thickness and five-year progression of carotid atherosclerosis, independently from standard risk factors for atherosclerosis. Experimentally, we analyzed the area of atherosclerotic lesions, femoral artery injury-induced re-endothelialization and neointima formation in both DKK3/ApoE and DKK3/ApoE mice. It was demonstrated that DKK3 deficiency accelerated atherosclerosis and delayed re-endothelialization with consequently exacerbated neointima formation. To explore the underlying mechanisms, we performed transwell and scratch migration assays using cultured human endothelial cells, which exhibited a significant induction in cell migration in response to DKK3 stimulation. This DKK3-induced migration was associated with activation of ROR2 and DVL1, activated Rac1 GTPases and upregulated JNK and c-jun phosphorylation in endothelial cells. Knockdown of ROR2 receptor using specific siRNA or transfection of a dominant negative form of Rac1 in endothelial cells markedly inhibited cell migration and downstream JNK and c-jun phosphorylation. CONCLUSIONS—: This study provides the evidence for a role of DKK3 in the protection against atherosclerosis involving endothelial migration and repair, with great therapeutic potential implications against atherosclerosis.Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited. © 2017 by the American College of Cardiology Foundation and the American Heart Association, Inc.


Wong M.M.,Kings College London Bhf Center | Hong X.,Kings College London Bhf Center | Karamariti E.,Kings College London Bhf Center | Hu Y.,Kings College London Bhf Center | Xu Q.,Kings College London Bhf Center
Journal of Visualized Experiments | Year: 2015

The construction of vascular conduits is a fundamental strategy for surgical repair of damaged and injured vessels resulting from cardiovascular diseases. The current protocol presents an efficient and reproducible strategy in which functional tissue engineered vessel grafts can be generated using partially induced pluripotent stem cell (PiPSC) from human fibroblasts. We designed a decellularized vessel scaffold bioreactor, which closely mimics the matrix protein structure and blood flow that exists within a native vessel, for seeding of PiPSC-endothelial cells or smooth muscle cells prior to grafting into mice. This approach was demonstrated to be advantageous because immune-deficient mice engrafted with the PiPSC-derived grafts presented with markedly increased survival rate 3 weeks after surgery. This protocol represents a valuable tool for regenerative medicine, tissue engineering and potentially patient-specific cell-therapy in the near future. © 2015 Journal of Visualized Experiments.

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