title: Tissue formation and tissue engineering through host cell recruitment or a potential injectable cell-based biocomposite with replicative potential: Molecular mechanisms controlling cellular senescence and the involvement of controlled transient telomerase activation therapies.
abstract: Accumulated data indicate that wound-care products should have a composition equivalent to that of the skin: a combination of particular growth factors and extracellular matrix (ECM) proteins endogenous to the skin, together with viable epithelial cells, fibroblasts, and mesenchymal stem cells (MSCs). Strategies consisting of bioengineered dressings and cell-based products have emerged for widespread clinical use; however, their performance is not optimal because chronic wounds persist as a serious unmet medical need. Telomerase, the ribonucleoprotein complex that adds telomeric repeats to the ends of chromosomes, is responsible for telomere maintenance, and its expression is associated with cell immortalization and, in certain cases, cancerogenesis. Telomerase contains a catalytic subunit, the telomerase reverse transcriptase (hTERT). Introduction of TERT into human cells extends both their lifespan and their telomeres to lengths typical of young cells. The regulation of TERT involves transcriptional and posttranscriptional molecular biology mechanisms. The manipulation, regulation of telomerase is multifactorial in mammalian cells, involving overall telomerase gene expression, post-translational protein-protein interactions, and protein phosphorylation. Reactive oxygen species (ROS) have been implicated in aging, apoptosis, and necrosis of cells in numerous diseases. Upon production of high levels of ROS from exogenous or endogenous generators, the redox balance is perturbed and cells are shifted into a state of oxidative stress, which subsequently leads to modifications of intracellular proteins and membrane lipid peroxidation and to direct DNA damage. When the oxidative stress is severe, survival of the cell is dependent on the repair or replacement of damaged molecules, which can result in induction of apoptosis in the injured with ROS cells. ROS-mediated oxidative stress induces the depletion of hTERT from the nucleus via export through the nuclear pores. Nuclear export is initiated by ROS-induced phosphorylation of tyrosine 707 within hTERT by the Src kinase family. It might be presumed that protection of mitochondria against oxidative stress is an important telomere length-independent function for telomerase in cell survival. Biotechnology companies are focused on development of therapeutic telomerase vaccines, telomerase inhibitors, and telomerase promoter-driven cell killing in oncology, have a telomerase antagonist in late preclinical studies. Anti-aging medicine-oriented groups have intervened on the market with products working on telomerase activation for a broad range of degenerative diseases in which replicative senescence or telomere dysfunction may play an important role. Since oxidative damage has been shown to shorten telomeres in tissue culture models, the adequate topical, transdermal, or systemic administration of antioxidants (such as, patented ocular administration of 1% N-acetylcarnosine lubricant eye drops in the treatment of cataracts) may be beneficial at preserving telomere lengths and delaying the onset or in treatment of disease in susceptible individuals. Therapeutic strategies toward controlled transient activation of telomerase are targeted to cells and replicative potential in cell-based therapies, tissue engineering and regenerative medicine.
authors.affiliation: Innovative Vision Products, Inc., 3511 Silverside Road, Suite 105, County of New Castle, Delaware, 19810.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Babizhayev
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow, 119991, Russian Federation.
authors.forename: Yegor E
authors.initials: YE
authors.lastname: Yegorov
mesh_terms: D000818:Animals; D001483:Base Sequence; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D016922:Cellular Senescence; D004789:Enzyme Activation; D006801:Humans; D008958:Models, Molecular; D044968:Regenerative Medicine / Q000379:methods; D019098:Telomerase / Q000032:analysis / Q000378:metabolism*; D016615:Telomere / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D059506:Telomere Shortening; D023822:Tissue Engineering / Q000379:methods*
chemical_list: D019098:Telomerase
keywords: aging; biological marker and bioassays; cell senescence and cell proliferation; cell-based therapies and regenerative medicine; lifespan; mitochondria; novel functions of human telomerase reverse transcriptase; telomerase; telomere shortening; telomere-dependent senescent phenotype; transcriptional and posttranscriptional mechanisms of telomerase regulation