Seeding of Vascular Grafts With Genetically Modified Endothelial Cells

Dunn, Peter F.; Newman, Kurt D.; Jones, Michael E.; Yamada, Izumi; Shayani, Vafa; Virmani, Renu; Dichek, David A.

doi:10.1161/01.cir.93.7.1439

Cited by 83 publications

(9 citation statements)

References 39 publications

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“…Once the graft is populated, endothelial progenitor cells can provide a native endothelial cell lining in addition to secreting basement membrane and signaling molecules for the subsequent trafficking of cytoactive factors [7,71,72,73]. Overall, endothelial cells “sense” both the topography and local compliance of their extracellular microenvironment, represented primarily by the basement membrane and actively respond to changes therein [29,30,74].…”

Section: Vascular Endothelial Cellsmentioning

confidence: 99%

Biophysical Cueing and Vascular Endothelial Cell Behavior

et al. 2010

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Human vascular endothelial cells (VEC) line the vessels of the body and are critical for the maintenance of vessel integrity and trafficking of biochemical cues. They are fundamental structural elements and are central to the signaling environment. Alterations in the normal functioning of the VEC population are associated with a number of vascular disorders among which are some of the leading causes of death in both the United States and abroad. VECs attach to their underlying stromal elements through a specialization of the extracellular matrix, the basement membrane. The basement membrane provides signaling cues to the VEC through its chemical constituents, by serving as a reservoir for cytoactive factors and through its intrinsic biophysical properties. This specialized matrix is composed of a topographically rich 3D felt-like network of fibers and pores on the nano (1–100 nm) and submicron (100–1,000 nm) size scale. The basement membrane provides biophysical cues to the overlying VECs through its intrinsic topography as well as through its local compliance (relative stiffness). These biophysical cues modulate VEC adhesion, migration, proliferation, differentiation, and the cytoskeletal signaling network of the individual cells. This review focuses on the impact of biophysical cues on VEC behaviors and demonstrates the need for their consideration in future vascular studies and the design of improved prosthetics.

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Section: Vascular Endothelial Cellsmentioning

confidence: 99%

Biophysical Cueing and Vascular Endothelial Cell Behavior

et al. 2010

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“…Glial fibrillary acidic protein, a marker of astroglial cells, increases with age (68), especially in the hippocampus and entorhinal cortex, which are susceptible to neurodegeneration in AD (69 -72). Astrocytosis, the proliferation and activation of astrocytes (73), is more pronounced in AD brains than in normal brains and usually occurs in areas surrounding neuritic plaques (74,75) and neurons bearing neurofibrillary tangles (75)(76)(77)(78). Importantly, activated astrocytes in AD brains secrete many cytokines, including interleukins 1 and 6, tumor necrosis factor-␣, and acute-phase inflammatory proteins, such as ␣ 2 -macroglobulin and C-reactive protein (79 -82).…”

Section: Fig 3 Regulation Of Apoe Expression In Neuro-2a Cells By Amentioning

confidence: 99%

Astroglial Regulation of Apolipoprotein E Expression in Neuronal Cells

Harris

Tesseur

Brecht

et al. 2004

Journal of Biological Chemistry

121

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Although apolipoprotein (apo) E is synthesized in the brain primarily by astrocytes, neurons in the central nervous system express apoE, albeit at lower levels than astrocytes, in response to various physiological and pathological conditions, including excitotoxic stress. To investigate how apoE expression is regulated in neurons, we transfected Neuro-2a cells with a 17-kilobase human apoE genomic DNA construct encoding apoE3 or apoE4 along with upstream and downstream regulatory elements. The baseline expression of apoE was low. However, conditioned medium from an astrocytic cell line (C6) or from apoE-null mouse primary astrocytes increased the expression of both isoforms by 3-4-fold at the mRNA level and by 4 -10-fold at the protein level. These findings suggest that astrocytes secrete a factor or factors that regulate apoE expression in neuronal cells. The increased expression of apoE was almost completely abolished by incubating neurons with U0126, an inhibitor of extracellular signal-regulated kinase (Erk), suggesting that the Erk pathway controls astroglial regulation of apoE expression in neuronal cells. Human neuronal precursor NT2/D1 cells expressed apoE constitutively; however, after treatment of these cells with retinoic acid to induce differentiation, apoE expression diminished. Cultured mouse primary cortical and hippocampal neurons also expressed low levels of apoE. Astrocyte-conditioned medium rapidly up-regulated apoE expression in fully differentiated NT2 neurons and in cultured mouse primary cortical and hippocampal neurons. Thus, neuronal expression of apoE is regulated by a diffusible factor or factors released from astrocytes, and this regulation depends on the activity of the Erk kinase pathway in neurons.The ⑀4 allele of the gene encoding apolipoprotein (apo) 1 E has been genetically linked to late-onset familial and sporadic Alzheimer's disease (AD) and has a gene-dose effect on the risk and age of onset of the disease (1-5). Individuals with two copies of the ⑀4 allele have a 50 -90% chance of developing AD by the age of 85, and those with one copy have about a 45% chance (1,6). Only about 20% of the general population develops AD by the age of 85 (1).ApoE is found in amyloid plaques and neurofibrillary tangles, two neuropathological hallmarks of AD (7-13), but its role in their pathogenesis is unclear. ApoE4 has several adverse effects that might explain the association between AD and the ⑀4 allele. It modulates the deposition and clearance of amyloid ␤ peptides and plaque formation (14 -21), impairs the antioxidative defense system (22), dysregulates neuronal signaling pathways (23), disrupts cytoskeletal structure and function (24,25), and alters the phosphorylation of tau and the formation of neurofibrillary tangles (26 -30). However, the mechanisms of these effects are still largely unknown, and it is not known which are the primary effects and which are subsequent or downstream effects.Initially, apoE was thought to be synthesized in the brain only by astrocytes, oligodendrocyte...

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“…LacZ expressing endothelial cells lining the luminal surface were demonstrated 5 weeks later. Later studies showed successful retroviral transduction of endothelial cells with proangiogenic genes such tissue-plasminogen activating (TPA) factor [88]. In a similar context, saphenous vein grafts could be successfully trans-duced using an adenoviral vector [89].…”

Section: Cartilagementioning

confidence: 99%

Gene transfer strategies in tissue engineering

Bleiziffer¹,

Eriksson

Yao

et al. 2007

J Cellular Molecular Medi

117

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Aiming for regeneration of severed or lost parts of the body, the combined application of gene therapy and tissue engineering has received much attention by regenerative medicine. Techniques of molecular biology can enhance the regenerative potential of a biomaterial by co-delivery of therapeutic genes, and several different strategies have been used to achieve that goal. Possibilities for application are many-fold and have been investigated to regenerate tissues such as skin, cartilage, bone, nerve, liver, pancreas and blood vessels. This review discusses advantages and problems encountered with the different gene delivery strategies as far as they relate to tissue engineering, analyses the positive aspects of polymeric gene delivery from matrices and discusses advances and future challenges of gene transfer strategies in selected tissues.

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Seeding of Vascular Grafts With Genetically Modified Endothelial Cells

Abstract: Increased TPA expression significantly decreases seeded EC adherence in vitro and in vivo. Gene therapy strategies for decreasing graft thrombosis may require expression of antithrombotic molecules that lack proteolytic activity.

Cited by 83 publications

References 39 publications

Biophysical Cueing and Vascular Endothelial Cell Behavior

Biophysical Cueing and Vascular Endothelial Cell Behavior

Astroglial Regulation of Apolipoprotein E Expression in Neuronal Cells

Gene transfer strategies in tissue engineering

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