Blood vessels engineered from human cells

Poh, Melissa Su Wei; Boyer, Matthew; Solan, Amy; Dahl, Shannon L. M.; Pedrotty, Dawn M.; Banik, Soma S. R.; McKee, Julia A.; Klinger, Rebecca Y.; Counter, Christopher M.; Niklason, Laura E.

doi:10.1016/s0140-6736(05)66735-9

Cited by 207 publications

(161 citation statements)

References 6 publications

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“…These proteins include heat-shock proteins p23 and Hsp90, PinX1 and p53, with p23 and Hsp90 being implicated in facilitating hTERT folding and telomerase holoenzyme assembly [65][66][67][68]. PinX1 as a telomere-binding protein associates with hTERT/hTERC complex in vitro and inhibits telomerase activity [69][70][71]. Moreover, p53 also associates with telomeres and inhibits telomerase [72][73][74][75].…”

Section: Molecular Mechanisms Regulating Telomerase Activitymentioning

confidence: 99%

Mechanisms of cell immortalization mediated by EB viral activation of telomerase in nasopharyngeal carcinoma

et al. 2006

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Nasopharyngeal carcinoma (NPC) is a common cancer in Southern China and Southeast Asia. The disease is a poorly differentiated carcinoma without effective cure, and the mechanism underlying its development remains largely unknown. Of several factors identified in NPC aetiology in recent years, Epstein-Barr virus (EBV) infection has emerged to be most important. In almost all NPC cells, EBV uses several intracellular mechanisms to cause oncogenic evolution of the infected cells. One such mechanism by which EBV infection induces cellular immortalization is believed to be through the activation of telomerase, an enzyme that is normally repressed but becomes activated during cancer development. Studies show that greater than 85% of primary NPC display high telomerase activity by mechanisms involving EBV infection, consistent with the notion that EBV is commonly involved in inducing cell immortalization. More recently, different EBV proteins have been shown to activate or inhibit the human telomerase reverse transcriptase gene, by modulating intracellular signalling pathways. These findings suggest a new model with a number of challenges towards our understanding, molecular targeting and therapeutic intervention in NPC.

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Section: Molecular Mechanisms Regulating Telomerase Activitymentioning

confidence: 99%

Mechanisms of cell immortalization mediated by EB viral activation of telomerase in nasopharyngeal carcinoma

et al. 2006

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“…However, a difficulty in using autologous cells lies in the restricted proliferative capacity of donor cells in vitro. For example, we have recently shown that a critical stumbling block to the clinical application of engineered small caliber vessels using autologous human cells is the limited proliferative lifespan of elderly vascular smooth muscle cells (SMC), which are the primary cellular constituent of engineered vessels and crucial for providing mechanical integrity (2). Vascular SMC that are obtained from elderly patients (those individuals beyond middle age and representing the age group most likely to require coronary revascularization) have an in vitro lifespan as low as 5-10 population doublings.…”

mentioning

confidence: 99%

“…Vascular SMC that are obtained from elderly patients (those individuals beyond middle age and representing the age group most likely to require coronary revascularization) have an in vitro lifespan as low as 5-10 population doublings. This short lifespan limits their utility for culturing functional blood vessels, because this process ultimately requires 30-40 population doublings (2)(3)(4). Vascular SMC and vascular tissue engineering thus represent an excellent model system for studying cellular lifespan with respect to its impact on tissue engineering.…”

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confidence: 99%

Relevance and safety of telomerase for human tissue engineering

Klinger

Blum

Hearn

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Tissue engineering holds the promise of replacing damaged or diseased tissues and organs. The use of autologous donor cells is often not feasible because of the limited replicative lifespan of cells, particularly those derived from elderly patients. Proliferative arrest can be overcome by the ectopic expression of telomerase via human telomerase reverse transcriptase (hTERT) gene transfection. To study the efficacy and safety of this potentially valuable technology, we used differentiated vascular smooth muscle cells (SMC) and vascular tissue engineering as a model system. Although we previously demonstrated that vessels engineered with telomerase-expressing SMC had improved mechanics over those grown with control cells, it is critical to assess the phenotypic impact of telomerase expression in donor cells, because telomerase upregulation is observed in >95% of human malignancies. To study the impact of telomerase in tissue engineering, expression of hTERT was retrovirally induced in SMC from eight elderly patients and one young donor. In hTERT SMC, significant lifespan extension beyond that of control was achieved without population doubling time acceleration. Karyotype changes were seen in both control and hTERT SMC but were not clonal nor representative of cancerous change. hTERT cells also failed to show evidence of neoplastic transformation in functional assays of tumorigenicity. In addition, the impact of donor age on cellular behavior, particularly the synthetic capability of SMC, was not affected by hTERT expression. Hence, this tissue engineering model system highlights the impact of donor age on cellular synthetic function that appears to be independent of lifespan extension by hTERT.tumorigenicity ͉ smooth muscle cells ͉ vascular graft

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“…While tissue engineering has shown promise for the development of patient-specific vascular substitutes, the use of autologous cells is limited by the decreased proliferative and functional capacity of cells isolated from many in the potential patient population, including older, diabetic, and hypertensive patients [166]. To overcome limitations in older patients, Poh et al transfected vascular cells isolated from these patients to express human telomerase reverse transcriptase (hTERT) [192]. hTERT is thought to improve the growth of somatic cells by restoring telomerase activity.…”

Section: Tissue Engineered Vascular Conduitsmentioning

confidence: 99%

Cardiovascular gene delivery: The good road is awaiting☆

Brewster

Brey

Greisler

2006

Advanced Drug Delivery Reviews

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Atherosclerotic cardiovascular disease is a leading cause of death worldwide. Despite recent improvements in medical, operative, and endovascular treatments, the number of interventions performed annually continues to increase. Unfortunately, the durability of these interventions is limited acutely by thrombotic complications and later by myointimal hyperplasia followed by progression of atherosclerotic disease over time. Despite improving medical management of patients with atherosclerotic disease, these complications appear to be persisting. Cardiovascular gene therapy has the potential to make significant clinical inroads to limit these complications. This article will review the technical aspects of cardiovascular gene therapy; its application for promoting a functional endothelium, smooth muscle cell growth inhibition, therapeutic angiogenesis, tissue engineered vascular conduits, and discuss the current status of various applicable clinical trials.

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Blood vessels engineered from human cells

Cited by 207 publications

References 6 publications

Mechanisms of cell immortalization mediated by EB viral activation of telomerase in nasopharyngeal carcinoma

Mechanisms of cell immortalization mediated by EB viral activation of telomerase in nasopharyngeal carcinoma

Relevance and safety of telomerase for human tissue engineering

Cardiovascular gene delivery: The good road is awaiting☆

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