J.W. Shay, W.E. Wright

Functional telomeres are essential for continued cell proliferation. Induction of telomere-based replicative senescence is caused by the lack of sufficient telomerase activity, and this leads to progressive telomere erosion with each replication (end-replication problem). Telomere shortening occurs as part of normal aging and this is enhanced in chronic diseases associated with increased cellular turnover. There is mounting correlative evidence that telomere shortening may be an important aspect of tissue dysfunction. The reverse transcriptase protein component of telomerase (hTERT) catalyzes the addition of telomeric sequences to the ends of chromosomes. Because telomerase activity is not found or is present in reduced amounts in somatic tissues, telomeres shorten with each cell division in almost all cells including proliferative cells of the skin, gastrointestinal system and blood. The expression of hTERT reconstitutes telomerase activity and circumvents the induction of senescence. We have used hTERT to immortalize a variety of human cell types such as human corneal fibroblasts/epithelial cells, skin keratinocytes/dermal fibroblasts, and bronchial epithelial cells/lung fibroblasts and used these to form organotypic cultures. Such organotypic cultures express differentiation-specific proteins, suggesting that hTERT does not inhibit normal differentiation functions of cells. The production of reversibily immortalized engineered cells offer the possibility of producing cells and tissues to treat a variety of chronic diseases and aged-related medical conditions that are due to telomere-based replicative senescence.

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tissue engineering