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Telomeres and Tissue Engineering: The Potential Roles of TERT in VEGF-mediated Angiogenesis

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An Erratum to this article was published on 09 May 2013

Abstract

Telomeres are protective structures located at the end of eukaryotic chromosomes which are shortened after each cell division, leading to senescence. Telomerase activity prevents telomere shortening by reverse transcription catalyzed by the subunit called TERT (telomerase reverse transcriptase). TERT expression has shown interesting cellular properties, which may be appealing for tissue engineering, such as the enhancement of cell proliferation and differentiation abilities in vitro. Despite some evidence for playing these roles in VEGF (vascular endothelial growth factor)-mediated angiogenesis, it is still unclear whether TERT can contribute to this essential event to generate functional organs. This review suggests a hypothesis that TERT and VEGF potentially regulates the transcriptional expression of each other, which would give new perspectives in the roles of telomerase in regulating several cellular processes, and also contributing for a better comprehension of the molecular mechanisms underlying VEGF signaling (both paracrine and autocrine). In general, based on the literature revised, it is possible to conclude that TERT is a potential VEGF enhancer; however, it is necessary to elaborate methodological approaches to explore this potential and to assess the potential benefits on tissue engineering approaches.

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References

  1. Martinez, P., & Blasco, M. A. (2011). Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins. Nature Reviews Cancer, 11, 161–176.

    Article  PubMed  CAS  Google Scholar 

  2. de Lange, L. T. (2005). Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Development, 19, 2100–2110.

    Article  PubMed  Google Scholar 

  3. Blackburn, E. H. (2005). Telomeres and telomerase: their mechanisms of action and the effects of altering their functions. FEBS Letters, 579, 859–862.

    Article  PubMed  CAS  Google Scholar 

  4. Pampalona, J., Soler, D., Genesca, A., & Tusell, L. (2010). Telomere dysfunction and chromosome structure modulate the contribution of individual chromosomes in abnormal nuclear morphologies. Mutation Research, 683, 16–22.

    Article  PubMed  CAS  Google Scholar 

  5. Pampalona, J., Soler, D., Genesca, A., & Tusell, L. (2010). Whole chromosome loss is promoted by telomere dysfunction in primary cells. Genes, Chromosomes and Cancer, 49, 368–378.

    CAS  Google Scholar 

  6. Hornsby, P. J. (2010). Cellular aging and cancer. Critical Reviews Oncology/Hematology, 79, 189–195.

    Article  Google Scholar 

  7. Deng, Y., Chan, S. S., & Chang, S. (2008). Telomere dysfunction and tumour suppression: the senescence connection. Nature Reviews Cancer, 8, 450–458.

    Article  PubMed  CAS  Google Scholar 

  8. Hayflick, L., & Moorhead, P. S. (1961). The serial cultivation of human diploid cell strains. Experimental Cell Research, 25, 585–621.

    Article  PubMed  CAS  Google Scholar 

  9. Olovnikov, A. M. (1973). A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. Journal of Theoretical Biology, 41, 181–190.

    Article  PubMed  CAS  Google Scholar 

  10. Good, P. I. (1977). Astochastic model for in vitro ageing II. A theory of marginotomy. Journal of Theoretical Biology, 64, 261–275.

    Article  PubMed  CAS  Google Scholar 

  11. Harley, C. B., Futcher, A. B., & Greider, C. W. (1990). Telomeres shorten during ageing of human fibroblasts. Nature, 345, 458–460.

    Article  PubMed  CAS  Google Scholar 

  12. Allsopp, R. C., Vaziri, H., Patterson, C., Goldstein, S., Younglai, E. V., Futcher, A. B., et al. (1992). Telomere length predicts replicative capacity of human fibroblasts. Proceedings of the National Academy of Sciences of the United States of America, 89, 10114–10118.

    Article  PubMed  CAS  Google Scholar 

  13. Wright, W. E., & Shay, J. W. (1992). The two-stage mechanism controlling cellular senescence and immortalization. Experimental Gerontology, 27, 383–389.

    Article  PubMed  CAS  Google Scholar 

  14. Maser, R. S., & Depinho, R. A. (2002). Connecting chromosomes, crisis, and cancer. Science, 297, 565–569.

    Article  PubMed  CAS  Google Scholar 

  15. Greider, C. W., & Blackburn, E. H. (1987). The telomere terminal transferase of Tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity. Cell, 51, 887–898.

    Article  PubMed  CAS  Google Scholar 

  16. Cohen, S. B., Graham, M. E., Lovrecz, G. O., Bache, N., Robinson, P. J., & Reddel, R. R. (2007). Protein composition of catalytically active human telomerase from immortal cells. Science, 315, 1850–1853.

    Article  PubMed  CAS  Google Scholar 

  17. Wright, W. E., Piatyszek, M. A., Rainey, W. E., Byrd, W., & Shay, J. W. (1996). Telomerase activity in human germline and embryonic tissues and cells. Developmental Genetics, 18, 173–179.

    Article  PubMed  CAS  Google Scholar 

  18. Liu, L., Bailey, S. M., Okuka, M., Munoz, P., Li, C., Zhou, L., et al. (2007). Telomere lengthening early in development. Nature Cell Biology, 9, 1436–1441.

    Article  PubMed  CAS  Google Scholar 

  19. Shay, J. W., & Bacchetti, S. (1997). A survey of telomerase activity in human cancer. European Journal of Cancer, 33, 787–791.

    Article  PubMed  CAS  Google Scholar 

  20. Belair, C. D., Yeager, T. R., Lopez, P. M., & Reznikoff, C. A. (1997). Telomerase activity: a biomarker of cell proliferation, not malignant transformation. Proceedings of the National Academy of Sciences of the United States of America, 94, 13677–13682.

    Article  PubMed  CAS  Google Scholar 

  21. Flores, I., Benetti, R., & Blasco, M. A. (2006). Telomerase regulation and stem cell behaviour. Current Opinion in Cell Biology, 18, 254–260.

    Article  PubMed  CAS  Google Scholar 

  22. Shukla, S., Acharya, S., Rajput, D., Vagha, S., & Grover, S. (2010). Telomere–the twilight to immortality. Journal of the Association of Physicians of India, 58, 553–560.

    PubMed  Google Scholar 

  23. Flores, I., Cayuela, M. L., & Blasco, M. A. (2005). Effects of telomerase and telomere length on epidermal stem cell behavior. Science, 309, 1253–1256.

    Article  PubMed  CAS  Google Scholar 

  24. Rossi, D. J., Bryder, D., Seita, J., Nussenzweig, A., Hoeijmakers, J., & Weissman, I. L. (2007). Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature, 447, 725–729.

    Article  PubMed  CAS  Google Scholar 

  25. Wong, K. K., Maser, R. S., Bachoo, R. M., Menon, J., Carrasco, D. R., Gu, Y., et al. (2003). Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature, 421, 643–648.

    Article  PubMed  CAS  Google Scholar 

  26. Ferron, S., Mira, H., Franco, S., Cano-Jaimez, M., Bellmunt, E., Ramirez, C., et al. (2004). Telomere shortening and chromosomal instability abrogates proliferation of adult but not embryonic neural stem cells. Development, 131, 4059–4070.

    Article  PubMed  CAS  Google Scholar 

  27. Ferron, S. R., Marques-Torrejon, M. A., Mira, H., Flores, I., Taylor, K., Blasco, M. A., et al. (2009). Telomere shortening in neural stem cells disrupts neuronal differentiation and neuritogenesis. Journal of Neuroscience, 29, 14394–14407.

    Article  PubMed  CAS  Google Scholar 

  28. Weinrich, S. L., Pruzan, R., Ma, L., Ouellette, M., Tesmer, V. M., Holt, S. E., et al. (1997). Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT. Nature Genetics, 17, 498–502.

    Article  PubMed  CAS  Google Scholar 

  29. Bodnar, A. G., Ouellette, M., Frolkis, M., Holt, S. E., Chiu, C. P., Morin, G. B., et al. (1998). Extension of life-span by introduction of telomerase into normal human cells. Science, 279, 349–352.

    Article  PubMed  CAS  Google Scholar 

  30. Laschke, M. W., Harder, Y., Amon, M., Martin, I., Farhadi, J., Ring, A., et al. (2006). Angiogenesis in tissue engineering: breathing life into constructed tissue substitutes. Tissue Engineering, 12, 2093–2104.

    Article  PubMed  CAS  Google Scholar 

  31. Demarco, F. F., Conde, M. C., Cavalcanti, B. N., Casagrande, L., Sakai, V. T., & Nor, J. E. (2011). Dental pulp tissue engineering. Brazilian Dental Journal, 22, 3–13.

    Article  PubMed  Google Scholar 

  32. Nedel, F., Andre, D. A., de Oliveira, I. O., Cordeiro, M. M., Casagrande, L., Tarquinio, S. B., et al. (2009). Stem cells: therapeutic potential in dentistry. Journal of Contemporary Dental Practice, 10, 90–96.

    PubMed  Google Scholar 

  33. Sakai, V. T., Cordeiro, M. M., Dong, Z., Zhang, Z., Zeitlin, B. D., & Nor, J. E. (2011). Tooth slice/scaffold model of dental pulp tissue engineering. Advances in Dental Research, 23, 325–332.

    Article  PubMed  CAS  Google Scholar 

  34. Hegen, A., Blois, A., Tiron, C. E., Hellesoy, M., Micklem, D. R., Nor, J. E., et al. (2011). Efficient in vivo vascularization of tissue-engineering scaffolds. Journal of Tissue Engineering and Regenerative Medicine, 5, e52–e62.

    Article  PubMed  CAS  Google Scholar 

  35. Senger, D. R., Galli, S. J., Dvorak, A. M., Perruzzi, C. A., Harvey, V. S., & Dvorak, H. F. (1983). Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science, 219, 983–985.

    Article  PubMed  CAS  Google Scholar 

  36. Koch, S., Tugues, S., Li, X., Gualandi, L., & Claesson-Welsh, L. (2011). Signal transduction by vascular endothelial growth factor receptors. Biochemical Journal, 437, 169–183.

    Article  PubMed  CAS  Google Scholar 

  37. Zeitlin, B. D., Ellis, L. M., & Nor, J. E. (2009). Inhibition of vascular endothelial growth factor receptor-1/Wnt/{beta}-catenin crosstalk leads to tumor cell death. Clinical Cancer Research, 15, 7453–7455.

    Article  PubMed  CAS  Google Scholar 

  38. Giordano, R. J., Cardo-Vila, M., Salameh, A., Anobom, C. D., Zeitlin, B. D., Hawke, D. H., et al. (2010). From combinatorial peptide selection to drug prototype (I): targeting the vascular endothelial growth factor receptor pathway. Proceedings of the National Academy of Sciences of the United States of America, 107, 5112–5117.

    Article  PubMed  CAS  Google Scholar 

  39. Armstrong, L., Saretzki, G., Peters, H., Wappler, I., Evans, J., Hole, N., et al. (2005). Overexpression of telomerase confers growth advantage, stress resistance, and enhanced differentiation of ESCs toward the hematopoietic lineage. Stem Cells, 23, 516–529.

    Article  PubMed  CAS  Google Scholar 

  40. Indran, I. R., Hande, M. P., & Pervaiz, S. (2011). hTERT overexpression alleviates intracellular ROS production, improves mitochondrial function, and inhibits ROS-mediated apoptosis in cancer cells. Cancer Research, 71, 266–276.

    Article  PubMed  CAS  Google Scholar 

  41. Yang, C., Przyborski, S., Cooke, M. J., Zhang, X., Stewart, R., Anyfantis, G., et al. (2008). A key role for telomerase reverse transcriptase unit in modulating human embryonic stem cell proliferation, cell cycle dynamics, and in vitro differentiation. Stem Cells, 26, 850–863.

    Article  PubMed  CAS  Google Scholar 

  42. Sirma, H., Kumar, M., Meena, J. K., Witt, B., Weise, J. M., Lechel, A., et al. (2011). The promoter of human telomerase reverse transcriptase is activated during liver regeneration and hepatocyte proliferation. Gastroenterology, 141(326–37), 337.

    Google Scholar 

  43. Liang, X. J., Chen, X. J., Yang, D. H., Huang, S. M., Sun, G. D., & Chen, Y. P. (2011). Differentiation of human umbilical cord mesenchymal stem cells into hepatocyte-like cells by hTERT gene transfection in vitro. Cell Biology International, 36, 215–221.

    Article  Google Scholar 

  44. He, X. Y., Zheng, Y. M., Lan, J., Wu, Y. H., Yan, J., He, X. N., et al. (2011). Recombinant adenovirus-mediated human telomerase reverse transcriptase gene can stimulate cell proliferation and maintain primitive characteristics in bovine mammary gland epithelial cells. Development, Growth & Differentiation, 53, 312–322.

    Article  CAS  Google Scholar 

  45. Tsai, C. C., Chen, C. L., Liu, H. C., Lee, Y. T., Wang, H. W., Hou, L. T., et al. (2010). Overexpression of hTERT increases stem-like properties and decreases spontaneous differentiation in human mesenchymal stem cell lines. Journal of Biomedical Science, 17, 64.

    Article  PubMed  Google Scholar 

  46. Mi, H. W., Lee, M. C., Fu, E., Chow, L. P., & Lin, C. P. (2011). Highly efficient multipotent differentiation of human periodontal ligament fibroblasts induced by combined BMP4 and hTERT gene transfer. Gene Therapy, 18, 452–461.

    Article  PubMed  CAS  Google Scholar 

  47. Asumda, F. Z., & Chase, P. B. (2011). Age-related changes in rat bone-marrow mesenchymal stem cell plasticity. BMC Cell Biology, 12, 44.

    Article  PubMed  CAS  Google Scholar 

  48. Tang, J., Wang, Z., Li, X., Li, J., & Shi, H. (2008). Human telomerase reverse transcriptase expression correlates with vascular endothelial growth factor-promoted tumor cell proliferation in prostate cancer. Artificial Cells, Blood Substitutes and Biotechnology, 36, 83–93.

    Article  CAS  Google Scholar 

  49. Kirkpatrick, K. L., Newbold, R. F., & Mokbel, K. (2004). The mRNA expression of hTERT in human breast carcinomas correlates with VEGF expression. Journal of Carcinogenesis, 3, 1.

    Article  PubMed  Google Scholar 

  50. Bermudez, Y., Yang, H., Saunders, B. O., Cheng, J. Q., Nicosia, S. V., & Kruk, P. A. (2007). VEGF- and LPA-induced telomerase in human ovarian cancer cells is Sp1-dependent. Gynecologic Oncolcology, 106, 526–537.

    Article  CAS  Google Scholar 

  51. Zhou, L., Zheng, D., Wang, M., & Cong, Y. S. (2009). Telomerase reverse transcriptase activates the expression of vascular endothelial growth factor independent of telomerase activity. Biochemical and Biophysical Research Communications, 386, 739–743.

    Article  PubMed  CAS  Google Scholar 

  52. Shkreli, M., Sarin, K. Y., Pech, M. F., Papeta, N., Chang, W., Brockman, S. A., et al. (2012). Reversible cell-cycle entry in adult kidney podocytes through regulated control of telomerase and Wnt signaling. Nature Medicine, 18, 111–119.

    Article  CAS  Google Scholar 

  53. Strong, M. A., Vidal-Cardenas, S. L., Karim, B., Yu, H., Guo, N., & Greider, C. W. (2011). Phenotypes in mTERT/ and mTERT/ mice are due to short telomeres, not telomere-independent functions of telomerase reverse transcriptase. Molecular and Cell Biology, 31, 2369–2379.

    Article  CAS  Google Scholar 

  54. Donnini, S., Solito, R., Cetti, E., Corti, F., Giachetti, A., Carra, S., et al. (2010). Abeta peptides accelerate the senescence of endothelial cells in vitro and in vivo, impairing angiogenesis. The Journal of the Federation of American Societies for Experimental Biology, 24, 2385–2395.

    CAS  Google Scholar 

  55. Minamino, T., & Komuro, I. (2008). Vascular aging: insights from studies on cellular senescence, stem cell aging, and progeroid syndromes. Nature Reviews Cardiology, 5, 637–648.

    CAS  Google Scholar 

  56. Zaccagnini, G., Gaetano, C., Della, P. L., Nanni, S., Grasselli, A., Mangoni, A., et al. (2005). Telomerase mediates vascular endothelial growth factor-dependent responsiveness in a rat model of hind limb ischemia. Journal of Biological Chemistry, 280, 14790–14798.

    Article  PubMed  CAS  Google Scholar 

  57. Baumer, Y., Funk, D., & Schlosshauer, B. (2010). Does telomerase reverse transcriptase induce functional de-differentiation of human endothelial cells? Cellular and Molecular Life Sciences, 67, 2451–2465.

    Article  PubMed  CAS  Google Scholar 

  58. Shi, A. W., Gu, N., Liu, X. M., Wang, X., & Peng, Y. Z. (2011). Ginsenoside rg1 enhances endothelial progenitor cell angiogenic potency and prevents senescence in vitro. Journal of International Medical Research, 39, 1306–1318.

    Article  PubMed  CAS  Google Scholar 

  59. Chang, E., & Harley, C. B. (1995). Telomere length and replicative aging in human vascular tissues. Proceedings of the National Academy of Sciences of the United States of America, 92, 11190–11194.

    Article  PubMed  CAS  Google Scholar 

  60. Fadini, G. P., & Avogaro, A. (2010). Cell-based methods for ex vivo evaluation of human endothelial biology. Cardiovascular Research, 87, 12–21.

    Article  PubMed  CAS  Google Scholar 

  61. Yoder, M. C. (2010). Is endothelium the origin of endothelial progenitor cells? Arteriosclerosis, Thrombosis, and Vascular Biology, 30, 1094–1103.

    Article  PubMed  CAS  Google Scholar 

  62. Lee, S., Chen, T. T., Barber, C. L., Jordan, M. C., Murdock, J., Desai, S., et al. (2007). Autocrine VEGF signaling is required for vascular homeostasis. Cell, 130, 691–703.

    Article  PubMed  CAS  Google Scholar 

  63. Harley, C. B., Liu, W., Blasco, M., Vera, E., Andrews, W. H., Briggs, L. A., et al. (2011). A natural product telomerase activator as part of a health maintenance program. Rejuvenation Research, 14, 45–56.

    Article  PubMed  CAS  Google Scholar 

  64. de Jesus, B.B., Schneeberger, K., Vera, E., Tejera, A., Harley, C.B., & Blasco, M.A. (2011). The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence. Aging Cell

  65. Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144, 646–674.

    Article  PubMed  CAS  Google Scholar 

  66. Xie, M., Chen, Q., He, S., Li, B., & Hu, C. (2011). Silencing of the human TERT gene by RNAi inhibits A549 lung adenocarcinoma cell growth in vitro and in vivo. Oncology Reports, 26, 1019–1027.

    PubMed  CAS  Google Scholar 

  67. Kotsakis, A., Vetsika, E. K., Christou, S., Hatzidaki, D., Vardakis, N., Aggouraki, D., et al. (2012). Clinical outcome of patients with various advanced cancer types vaccinated with an optimized cryptic human telomerase reverse transcriptase (TERT) peptide: results of an expanded phase II study. Annals of Oncology, 23, 442–449.

    Article  PubMed  CAS  Google Scholar 

  68. Feldser, D. M., Hackett, J. A., & Greider, C. W. (2003). Telomere dysfunction and the initiation of genome instability. Nature Reviews Cancer, 3, 623–627.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Fernanda Nedel or Flávio F. Demarco.

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Hartwig, F.P., Nedel, F., Collares, T.V. et al. Telomeres and Tissue Engineering: The Potential Roles of TERT in VEGF-mediated Angiogenesis. Stem Cell Rev and Rep 8, 1275–1281 (2012). https://doi.org/10.1007/s12015-012-9414-3

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