Relevance and safety of telomerase for human tissue engineering

Klinger, Rebecca Y.; Blum, Juliana L.; Hearn, Bevin; Lebow, Benjamin; Niklason, Laura E.

doi:10.1073/pnas.0508184103

Cited by 41 publications

(29 citation statements)

References 50 publications

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“…24,25 The effect of Ang II on ROS production, DNA damage, telomere attrition, and senescence was evaluated by supplementing culture medium with Ang II. For chronic exposure experiments, ie, up to 30 days, the medium overlying cells was supplemented with Ang II on alternate days.…”

Section: Methodsmentioning

confidence: 99%

Angiotensin II–Mediated Oxidative DNA Damage Accelerates Cellular Senescence in Cultured Human Vascular Smooth Muscle Cells via Telomere-Dependent and Independent Pathways

Herbert

Mistry

Hastings

et al. 2008

Circulation Research

155

129

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Abstract-Angiotensin II (Ang II) induces reactive oxygen species (ROS) production by human vascular smooth muscle cells (hVSMCs). ROS have been implicated in the development of both acute stress-induced premature senescence (SIPS) and chronic replicative senescence. Global oxidative DNA damage triggers SIPS and telomere DNA damage accelerates replicative senescence, both mediated via p53. This study tests the hypothesis that DNA is an important target for Ang II-induced ROS leading to senescence via telomere-dependent and independent pathways. DNA damage was quantified using the Comet assay, telomere DNA length by Southern blotting and hVSMC senescence by senescence-associated ␤-galactosidase staining. Exposure to Ang II increased DNA damage in hVSMCs within 4 hours. Inhibition by an AT 1 receptor antagonist (losartan metabolite: E3174) or catalase, confirmed that Ang II-induced DNA damage was AT 1 receptor-mediated, via the induction of ROS. Acute exposure to Ang II resulted in SIPS within 24 hours that was prevented by coincubation with E3174 or catalase. SIPS was associated with increased p53 expression but was not dependent on telomere attrition because overexpression of human telomerase did not prevent Ang II-induced SIPS. Exposure to Ang II over several population doublings accelerated the rate of telomere attrition (by Ͼ2-fold) and induced premature replicative senescence of hVSMCs-an effect that was also attenuated by E3174 or catalase. These data demonstrate that Ang II-induced ROS-mediated DNA damage results in accelerated biological aging of hVSMCs via 2 mechanisms: (1) Acute SIPS, which is telomere independent, and (2) accelerated replicative senescence which is associated with accelerated telomere attrition.

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Section: Methodsmentioning

confidence: 99%

Angiotensin II–Mediated Oxidative DNA Damage Accelerates Cellular Senescence in Cultured Human Vascular Smooth Muscle Cells via Telomere-Dependent and Independent Pathways

Herbert

Mistry

Hastings

et al. 2008

Circulation Research

155

129

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“…Of note in this regard, hTERT overexpression in VSMCs from elderly patients does not lead to a transformed phenotype at population doubling Յ100. 148 The potential side effects of telomerase gene transfer could be limited by either using donor cells with conditional hTERT overexpression or telomerase-competent CSCs.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Telomere Biology and Cardiovascular Disease

Fuster

Andrés

2006

Circulation Research

213

201

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Abstract-Accumulation of cellular damage with advancing age leads to atherothrombosis and associated cardiovascular disease. Ageing is also characterized by shortening of the DNA component of telomeres, the specialized genetic segments located at the end of eukaryotic chromosomes that protect them from end-to-end fusions. By inducing genomic instability, replicative senescence and apoptosis, shortening of the telomeric DNA is thought to contribute to organismal ageing. In this Review, we discuss experimental and human studies that have linked telomeres and associated proteins to several factors which influence cardiovascular risk (eg, estrogens, oxidative stress, hypertension, diabetes, and psychological stress), as well as to neovascularization and the pathogenesis of atherosclerosis and heart disease. Two chief questions that remain unanswered are whether telomere shortening is cause or consequence of cardiovascular disease, and whether therapies targeting the telomere may find application in treating these disorders (eg, cell "telomerization" to engineer blood vessels of clinical value for bypass surgery, and to facilitate cell-based myocardial regeneration strategies). Given that most research to date has focused on the role of telomerase, it is also of up most importance to investigate whether alterations in additional telomere-associated proteins may contribute to the pathogenesis of cardiovascular disease. Key Words: telomeres Ⅲ telomerase Ⅲ atherosclerosis Ⅲ heart disease Ⅲ oxidative stress Ⅲ hypertension Ⅲ diabetes Ⅲ estrogens T elomeres are special chromatin structures located at the ends of eukaryotic chromosomes that prevent the recognition of chromosomal ends as double-stranded DNA breaks, thereby protecting these regions from recombination and degradation and avoiding a DNA damage cellular response. The telomeric DNA is composed of noncoding doublestranded repeats of G-rich tandem DNA sequences (TTAGGG in vertebrates) that are extended several thousand base pairs (10 to 15 kb in humans and 25 to 40 kb in mice) and end in a 150 to 200 nucleotide 3Ј single-stranded overhang (G-strand overhang) (Figure 1). 1,2 Several specific proteins are associated to telomeric DNA, including telomerase and the telomeric repeat binding factors 1 and 2 (TRF1, TRF2) which directly bind to the TTAGGG repeat and interact with other factors forming large protein complexes that regulate telomere length and structure. Mammalian telomerase consists of a RNA component (telomerase RNA component [TERC]) that serves as a template for the synthesis of new telomeric TTAGGG repeats by the telomerase reverse transcriptase component (TERT). Telomere components and structure has been comprehensively discussed elsewhere. 2

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“…A variety of hTERT-modified cells have been used in experimental cell therapy (Ulaner, 2004). A notable recent example is the construction of blood vessels engineered with hTERT-expressing smooth muscle cells (Klinger et al, 2006). Distinguishing the mechanisms by which hTERT affects cell proliferation versus cell function will be important so that the desirable features of each may be separately controlled.…”

Section: The Potential Role Of Telomerase In Cell Therapy In Agingmentioning

confidence: 99%

Telomerase and the aging process

Hornsby¹

2007

Experimental Gerontology

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The level of telomerase activity is important in determining telomere length in aging cells and tissues. Here evidence on the importance of telomerase activity is reviewed with respect to aging rates of mammalian species and the health and life span of individuals within a species. The significance of telomerase reactivation for both cancer development and for immortalizing cells for therapeutic processes is assessed. KeywordsTelomerase; telomeres; senescence; cancer; immortalization Telomeres are the specialized repetitive DNA sequences at the ends of the linear chromosomes, and associated proteins, that serve to maintain the integrity of the chromosomes. Telomerase is a ribonucleoprotein DNA polymerase complex that maintains telomere length. The complex comprises the protein telomerase reverse transcriptase (TERT, or hTERT in humans) and a catalytic RNA (TERC) (Shay and Wright, 2007). In the absence of telomerase activity telomeres progressively shorten. Telomerase activity is absent in most normal human somatic cells because of the lack of expression of TERT; TERC is usually present. On the other hand most mouse cells have telomerase activity (Blasco, 2005). Without telomerase, telomere shortening eventually limits the growth of cells, either by senescence, in cells with intact cell cycle checkpoints (a G1 cell cycle block), or by crisis in cells with inactivated checkpoints (telomeric end-to-end fusions cause chromosome breakage and mitotic catastrophe) (Shay and Wright, 2007). Expression of TERT in cells that otherwise lack telomerase activity causes cells to bypass senescence and crisis, and such cells are usually termed "immortalized." The significance of senescence, crisis and immortalization is explored further in this revew (see Figure 1). Do telomere biology and telomerase activity determine aging?The first aspect to this question is whether differences in aging rates among mammalian species are caused in whole or in part by species-specific differences in telomerase/telomere biology. A very brief consideration of this question will show that this is unlikely. Mice are short-lived compared to humans, yet mice have long telomeres and adult mouse somatic cells often have telomerase activity (Blasco, 2005). On the other hand, humans have relatively short telomeres, even when compared to closely related primates (Kakuo et al., 1999), and telomerase activity

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Relevance and safety of telomerase for human tissue engineering

Cited by 41 publications

References 50 publications

Angiotensin II–Mediated Oxidative DNA Damage Accelerates Cellular Senescence in Cultured Human Vascular Smooth Muscle Cells via Telomere-Dependent and Independent Pathways

Angiotensin II–Mediated Oxidative DNA Damage Accelerates Cellular Senescence in Cultured Human Vascular Smooth Muscle Cells via Telomere-Dependent and Independent Pathways

Telomere Biology and Cardiovascular Disease

Telomerase and the aging process

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