Why Use Telomerized Cells for Organ Transplantation

TELOMERES ARE SPECIALIZED STRUCTURES at the physical ends of eukaryotic chromosomes consisting of essential proteins and highly conserved repeated DNA sequences. Telomere loss occurs with each round of DNA replication based on the inability of DNA polymerases to completely replicate linear DNA molecules.1 Normal somatic cells undergo only a finite number of cell divisions in vitro before entering a non-dividing state called cellular senescence.2 Senescence is characterized by an irreversible arrest of cell proliferation, substantial alterations in patterns of gene expression (i.e., SAGE: senescence-associated gene expression), cell-type-specific changes in cell function and gene expression,3 an increasing resistance to apoptosis, and telomere shortening.4 The reduction in proliferative capacity of cells from old donors and patients with premature aging syndromes and the accumulation in vivo of senescent cells with altered patterns of gene expression implicate cellular senescence in aging and age-related pathologies.5 Following the death of senescent cells, cell division of neighboring mitotic cells can occur, and their division to fill in the gaps left by senesced cells may cause their own telomeres to shorten in the process. Thus, senescence can lead to a propagating cycle of accelerated aging among remaining cells.5 The telomere hypothesis of cellular aging proposes that telomere shortening in mitotic cells leads to their senescence and hastens the senescence of neighboring mitotic and post-mitotic cells.5 The presence of senescent cells may interfere with the normal functioning of organs and tissues, and contribute to their accelerated aging.6 The hypothesis suggests that if cell senescence can be prevented, then age-related diseases can also be prevented.7 Telomeres can be elongated by the ribonucleoprotein enzyme telomerase, which adds tandem hexanucleotide (TTAGGG)n repeats de novo to 39 ends of mammalian telomeres using its own RNA as a template.8 Telomerase comprises an RNA component, (hTR: human telomerase RNA) and protein component (hTRT: human telomerase reverse transcriptase). The RNA component is expressed in all cell types, whereas expression of the protein component (and concomitant telomerase activity) is restricted to specific cell types, such as germline, cancer, and stem cells. The action of telomerase compensates for the continual shortening of telomeres that would otherwise occur. In vitro reconstitution of telomerase into several diverse human cell types results in extension of cellular life-span, avoidance of cellular senescence, restoration of replicative potential,9 and reversion of gene expression to youthful levels3 in the absence of tumorigenic changes.10–12 Allogeneic (between individuals) organ/tissue transplants offer a lifesaving treatment for thousands of patients each year. The long-term survival of such grafts may be limited by (for example) cellular senescence of the graft cells themselves,13 host-versus-graft disease (when host T-cells recognize the graft as foreign and attempt to destroy it), and graft-versus-host disease (when T-cells present within the graft