Nitric Oxide Synthase Gene Transfer Restores Activity of Circulating Angiogenic Cells From Patients With Coronary Artery Disease

Ward, Michael R.; Thompson, Kathleen; Isaac, Kathryn V.; Vecchiarelli, Jonathan; Zhang, Qiuwang; Stewart, Duncan J.; Kutryk, Michael J.B.

doi:10.1038/mt.2011.52

Cited by 38 publications

(46 citation statements)

References 38 publications

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“…The idea of modifying stem cell-endothelial cells to improve therapeutic utility is not new [10], [35]. Thus, characterisation and modification of stem cell-endothelial cells at the level of TLR4 and other pattern recognition receptors represents a potentially important target for optimal and tailored cell therapy design.…”

Section: Discussionmentioning

confidence: 99%

Pathogen Sensing Pathways in Human Embryonic Stem Cell Derived-Endothelial Cells: Role of NOD1 Receptors

et al. 2014

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Human embryonic stem cell-derived endothelial cells (hESC-EC), as well as other stem cell derived endothelial cells, have a range of applications in cardiovascular research and disease treatment. Endothelial cells sense Gram-negative bacteria via the pattern recognition receptors (PRR) Toll-like receptor (TLR)-4 and nucleotide-binding oligomerisation domain-containing protein (NOD)-1. These pathways are important in terms of sensing infection, but TLR4 is also associated with vascular inflammation and atherosclerosis. Here, we have compared TLR4 and NOD1 responses in hESC-EC with those of endothelial cells derived from other stem cells and with human umbilical vein endothelial cells (HUVEC). HUVEC, endothelial cells derived from blood progenitors (blood outgrowth endothelial cells; BOEC), and from induced pluripotent stem cells all displayed both a TLR4 and NOD1 response. However, hESC-EC had no TLR4 function, but did have functional NOD1 receptors. In vivo conditioning in nude rats did not confer TLR4 expression in hESC-EC. Despite having no TLR4 function, hESC-EC sensed Gram-negative bacteria, a response that was found to be mediated by NOD1 and the associated RIP2 signalling pathways. Thus, hESC-EC are TLR4 deficient but respond to bacteria via NOD1. This data suggests that hESC-EC may be protected from unwanted TLR4-mediated vascular inflammation, thus offering a potential therapeutic advantage.

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Section: Discussionmentioning

confidence: 99%

Pathogen Sensing Pathways in Human Embryonic Stem Cell Derived-Endothelial Cells: Role of NOD1 Receptors

et al. 2014

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“…Integrin b 1 was chosen for use in the present study in an effort to facilitate homing of the ECFCs to the ischemic tissue, which would be expected to abundantly express ECM. Although ECFCs have been genetically modified in a number of earlier studies, most of those involved overexpression of angiogenic factors (e.g., vascular endothelial growth factor, hypoxia inducible factor-1a, hepatocyte growth factor, or endothelial nitric oxide synthase) in an effort to strengthen or accelerate the angiogenic function of ECFCs, not to facilitate homing [27][28][29][30][31][32]. Our approach might be unique in that context.…”

Section: Discussionmentioning

confidence: 99%

Intravenous Administration of Endothelial Colony-Forming Cells Overexpressing Integrin β1 Augments Angiogenesis in Ischemic Legs

Goto

Takemura

Takahashi

et al. 2015

Stem Cells Translational Medicine

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When injected directly into ischemic tissue in patients with peripheral artery disease, the reparative capacity of endothelial progenitor cells (EPCs) appears to be limited by their poor survival. We, therefore, attempted to improve the survival of transplanted EPCs through intravenous injection and gene modification. We anticipated that overexpression of integrin b 1 will enable injected EPCs to home to ischemic tissue, which abundantly express extracellular matrix proteins, the ligands for integrins. In addition, integrin b 1 has an independent angiogenesis-stimulating function. Human endothelial colony-forming cells (ECFCs; late-outgrowth EPCs) were transduced using a lentiviral vector encoding integrin b 1 (ITGB1) or enhanced green fluorescent protein (GFP). We then locally or systemically injected phosphate-buffered saline or the genetically modified ECFCs (GFP-ECFCs or ITGB1-ECFCs; 1 3 10 5 cells each) into NOD/Shi-scid, IL-2Rgnull mice whose right femoral arteries had been occluded 24 hours earlier. Upregulation of extracellular matrix proteins, including fibronectin, was apparent in the ischemic legs. Four weeks later, blood perfusion of the ischemic limb was significantly augmented only in the ITGB1-ECFC group. Scanning electron microscopy of vascular casts revealed increases in the perfused blood vessels in the ischemic legs of mice in the ITGB1-ECFC group and significant increases in the density of both capillaries and arterioles. Transplanted ECFC-derived vessels accounted for 28% 6 4.2% of the vessels in the ITGB1-ECFC group, with no cell fusion. Intravenous administration of ECFCs engineered to home to ischemic tissue appears to efficiently mediate therapeutic angiogenesis in a mouse model of peripheral artery disease. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:218-226 SIGNIFICANCEThe intravenous administration of endothelial colony-forming cells (ECFCs) genetically modified to overexpress integrin b 1 effectively stimulated angiogenesis in ischemic mouse hindlimbs. Transplanted ECFCs were observed in the ischemic leg tissue, even at the chronic stage. Moreover, the cells appeared functional, as evidenced by the improved blood flow. The cell type used (ECFCs), the route of administration (intravenous, not directly injected into the affected area), and the use of ligand-receptor interactions (extracellular matrix and integrins) for homing represent substantial advantages over previously reported cell therapies for the treatment of peripheral artery disease.

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“…Witkowski et al showed that the number CD34 ϩ hematopoietic CACs decreased with 10 days of short-term reduced physical activity (rPA) in older, highly trained men, and that the change in CD34 ϩ /VEGFR2 ϩ cells in peripheral blood significantly predicted the change in the reactive hyperemic forearm blood flow response with reduced activity (57). NO has been shown to be necessary for proper cell migration and neovascularization in some CAC types (22,27,55) and is deficient in cardiometabolic disease states (12,58). CAC NO production can be influenced by activity and expression of endothelial nitric oxide synthase (eNOS), the enzyme that catalyzes the production of NO.…”

mentioning

confidence: 99%

Circulating angiogenic cell population responses to 10 days of reduced physical activity

Guhanarayan

Jablonski

Witkowski

2014

Journal of Applied Physiology

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Circulating angiogenic cells (CACs) are a diverse group that have been identified as predictors of cardiovascular health and are inversely proportional to cardiovascular disease (CVD) outcomes. Inactivity is a growing concern in industrialized nations and is an independent risk factor for CVD. There is limited evidence regarding the impact of reduced physical activity (rPA) on different CAC populations. The purpose of this study was to evaluate the effect of objectively monitored rPA with maintained energy balance on two CAC populations (CFU and CD34(+) cells), intracellular nitric oxide (NOi), and genes related to NO production in active, healthy men. Participants (age 25 ± 2.9 yr) refrained from structured physical activity for 10 days, which was reflected by a significant reduction in time in vigorous + very vigorous intensity activity (P = 0.03). Sedentary time tended to increase (P = 0.06) with rPA. CFU CACs have been characterized as mainly monocytic and lymphocytic cells. We found significant reductions in both the number of CFU CACs (-35.69%, P = 0.01) and CFU CAC NOi (-33.84%, P = 0.03). Neither NOi nor the number of CD34(+) cells, which are hematopoietic and endothelial progenitors, changed with rPA. We found no significant differences in NO-related gene expression or oxidative stress-related gene expression with rPA in either CAC type. Therefore, we conclude that although various CAC populations have been related to vascular health, regular physical activity is necessary to maintain CAC NOi and the vulnerability of CACs to short-term reductions in physical activity is population specific.

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Nitric Oxide Synthase Gene Transfer Restores Activity of Circulating Angiogenic Cells From Patients With Coronary Artery Disease

Cited by 38 publications

References 38 publications

Pathogen Sensing Pathways in Human Embryonic Stem Cell Derived-Endothelial Cells: Role of NOD1 Receptors

Pathogen Sensing Pathways in Human Embryonic Stem Cell Derived-Endothelial Cells: Role of NOD1 Receptors

Intravenous Administration of Endothelial Colony-Forming Cells Overexpressing Integrin β1 Augments Angiogenesis in Ischemic Legs

Circulating angiogenic cell population responses to 10 days of reduced physical activity

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