Published online before print August 12, 2002, doi: 10.1161/01.CIR.0000027584.85865.B4
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2002;106:1133.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Constitutive Human Telomerase Reverse Transcriptase Expression Enhances Regenerative Properties of Endothelial Progenitor Cells
From the Department of Medicine (Vascular Medicine, Cardiology, Cardiovascular Research), St Elizabeth’s Medical Center, Tufts University School of Medicine (S.M., J.L., M.S., J.M.I., D.W.L., T.A.), Boston, Mass; Stem Cell Translational Research, Kobe Institute of Biomedical Research and Innovation/Riken Center for Developmental Biology (S.M., T.A.), Kobe, Japan; Department of Physiology, Tokai University School of Medicine (T.A.), Kanagawa, Japan.
Correspondence to Douglas W. Losordo, MD, or Takayuki Asahara, MD, PhD, St Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail douglas.losordo{at}tufts.edu or asa777@aol.com
Background— The regulatory molecule for cell life span, telomerase, was modified by human telomerase reverse transcriptase (hTERT) gene transfer to investigate its effect on regenerative properties of endothelial progenitor cells (EPCs) in neovascularization.
Methods and Results— Telomerase activity was enhanced in hTERT-transduced EPCs (Td-TERTs) (1.2-fold versus no transduced EPCs [no-Td] and 1.2-fold versus GFP-transduced EPCs [Td/GFPs] at day 8; 5.2-fold versus no-Td and 4.8-fold versus Td/GFP at day 21, respectively) Mitogenic capacity in Td/TERTs exceeded that in Td/GFPs at day 8 (0.62±0.02 versus 0.53±0.01, respectively; P<0.01). Vascular endothelial growth factor-induced cell migration in EPCs was markedly enhanced by hTERT overexpression (Td/TERTs versus Td/GFPs, 292±12 versus 174±6 cells, respectively; P<0.01). hTERT overexpression has rescued EPCs from starvation-induced cell apoptosis, an outcome that was further enhanced in response to vascular endothelial growth factor. The colony appearance of totally differentiated endothelial cells (tdECs) was detected before day 30 only in Td/TERT, whereas no tdEC colonies could be detected in both Td/GFPs and no-Tds. Finally, we investigated in vivo transplantation of heterologous EPCs. Td/TERTs dramatically improved postnatal neovascularization in terms of limb salvage by 4-fold in comparison with that of Td/GFPs; limb perfusion was measured by laser Doppler (0.77±0.10 versus 0.47±0.06; P=0.02), and capillary density (224±78 versus 90±40 capillaries/mm2; P<0.01).
Conclusions— These findings provide the novel evidence that telomerase activity contributes to EPC angiogenic properties; mitogenic activity, migratory activity, and cell survival. This enhanced regenerative activity of EPCs by hTERT transfer will provide novel therapeutical strategy for postnatal neovascularization in severe ischemic disease patients.
Key Words: telomerase • gene therapy • stem cells, endothelial • angiogenesis • ischemia
This article has been cited by other articles:
 |
|
 |
|
  M. R. Ward and D. J. Stewart Erythropoietin and mesenchymal stromal cells in angiogenesis and myocardial regeneration: one plus one equals three? Cardiovasc Res, June 25, 2008; (2008) cvn153v2. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Dimmeler and A. Leri Aging and Disease as Modifiers of Efficacy of Cell Therapy Circ. Res., June 6, 2008; 102(11): 1319 - 1330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kinnaird, E. Stabile, S. Zbinden, M.-S. Burnett, and S. E. Epstein Cardiovascular risk factors impair native collateral development and may impair efficacy of therapeutic interventions Cardiovasc Res, May 1, 2008; 78(2): 257 - 264. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. F. Alvarez, L. Huang, J. A. King, M. K. ElZarrad, M. C. Yoder, and T. Stevens Lung microvascular endothelium is enriched with progenitor cells that exhibit vasculogenic capacity Am J Physiol Lung Cell Mol Physiol, March 1, 2008; 294(3): L419 - L430. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Tang, J. Lu, J. P. Walterscheid, H.-H. Chen, D. A. Engler, T. Sawamura, P.-Y. Chang, H. J. Safi, C.-Y. Yang, and C.-H. Chen Electronegative LDL circulating in smokers impairs endothelial progenitor cell differentiation by inhibiting Akt phosphorylation via LOX-1 J. Lipid Res., January 1, 2008; 49(1): 33 - 47. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. W. Losordo, R. A. Schatz, C. J. White, J. E. Udelson, V. Veereshwarayya, M. Durgin, K. K. Poh, R. Weinstein, M. Kearney, M. Chaudhry, et al. Intramyocardial Transplantation of Autologous CD34+ Stem Cells for Intractable Angina: A Phase I/IIa Double-Blind, Randomized Controlled Trial Circulation, June 26, 2007; 115(25): 3165 - 3172. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kubo, T.-S. Li, R. Suzuki, M. Ohshima, S.-L. Qin, and K. Hamano Short-term pretreatment with low-dose hydrogen peroxide enhances the efficacy of bone marrow cells for therapeutic angiogenesis Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2582 - H2588. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Fuster and V. Andres Telomere Biology and Cardiovascular Disease Circ. Res., November 24, 2006; 99(11): 1167 - 1180. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Hamada, M. K. Kim, A. Iwakura, M. Ii, T. Thorne, G. Qin, J. Asai, Y. Tsutsumi, H. Sekiguchi, M. Silver, et al. Estrogen Receptors {alpha} and {beta} Mediate Contribution of Bone Marrow-Derived Endothelial Progenitor Cells to Functional Recovery After Myocardial Infarction Circulation, November 21, 2006; 114(21): 2261 - 2270. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Fujii, S.-H. Li, P. E. Szmitko, P. W.M. Fedak, and S. Verma C-Reactive Protein Alters Antioxidant Defenses and Promotes Apoptosis in Endothelial Progenitor Cells Arterioscler. Thromb. Vasc. Biol., November 1, 2006; 26(11): 2476 - 2482. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ishikawa, M. Eguchi, M. Wada, Y. Iwami, K. Tono, H. Iwaguro, H. Masuda, T. Tamaki, and T. Asahara Establishment of a Functionally Active Collagen-Binding Vascular Endothelial Growth Factor Fusion Protein In Situ Arterioscler. Thromb. Vasc. Biol., September 1, 2006; 26(9): 1998 - 2004. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Qin, R. Kishore, C. M. Dolan, M. Silver, A. Wecker, C. N. Luedemann, T. Thorne, A. Hanley, C. Curry, L. Heyd, et al. Cell cycle regulator E2F1 modulates angiogenesis via p53-dependent transcriptional control of VEGF PNAS, July 18, 2006; 103(29): 11015 - 11020. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kobayashi, T. Kondo, N. Inoue, M. Aoki, M. Mizuno, K. Komori, J. Yoshida, and T. Murohara Combination of In Vivo Angiopoietin-1 Gene Transfer and Autologous Bone Marrow Cell Implantation for Functional Therapeutic Angiogenesis Arterioscler. Thromb. Vasc. Biol., July 1, 2006; 26(7): 1465 - 1472. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T.-S. Li, A. Furutani, M. Takahashi, M. Ohshima, S.-L. Qin, T. Kobayashi, H. Ito, and K. Hamano Impaired potency of bone marrow mononuclear cells for inducing therapeutic angiogenesis in obese diabetic rats Am J Physiol Heart Circ Physiol, April 1, 2006; 290(4): H1362 - H1369. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. G.P. Welt and D. W. Losordo Cell Therapy for Acute Myocardial Infarction: Curb Your Enthusiasm? Circulation, March 14, 2006; 113(10): 1272 - 1274. [Full Text] [PDF]
|
|
|
|
|
|
D. M. Smadja, I. Bieche, G. Uzan, H. Bompais, L. Muller, C. Boisson-Vidal, M. Vidaud, M. Aiach, and P. Gaussem PAR-1 Activation on Human Late Endothelial Progenitor Cells Enhances Angiogenesis In Vitro With Upregulation of the SDF-1/CXCR4 System Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2321 - 2327. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Nishiyama, K. Takaji, K. Kataoka, Y. Kurihara, M. Yoshimura, A. Kato, H. Ogawa, and H. Kurihara Id1 Gene Transfer Confers Angiogenic Property on Fully Differentiated Endothelial Cells and Contributes to Therapeutic Angiogenesis Circulation, November 1, 2005; 112(18): 2840 - 2850. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Gulati and R. D. Simari Cell Therapy for Angiogenesis: Embracing Diversity Circulation, September 13, 2005; 112(11): 1522 - 1524. [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Ingram, N. M. Caplice, and M. C. Yoder Unresolved questions, changing definitions, and novel paradigms for defining endothelial progenitor cells Blood, September 1, 2005; 106(5): 1525 - 1531. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Siepe, C. Heilmann, P. von Samson, P. Menasche, and F. Beyersdorf Stem cell research and cell transplantation for myocardial regeneration Eur. J. Cardiothorac. Surg., August 1, 2005; 28(2): 318 - 324. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. J. Dzau, M. Gnecchi, A. S. Pachori, F. Morello, and L. G. Melo Therapeutic Potential of Endothelial Progenitor Cells in Cardiovascular Diseases Hypertension, July 1, 2005; 46(1): 7 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-J. Cho, S.-W. Youn, S.-I. Cheon, T.-Y. Kim, J. Hur, S.-Y. Zhang, S. P. Lee, K.-W. Park, M.-M. Lee, Y.-S. Choi, et al. Regulation of Endothelial Cell and Endothelial Progenitor Cell Survival and Vasculogenesis by Integrin-Linked Kinase Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1154 - 1160. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Edo and V. Andres Aging, telomeres, and atherosclerosis Cardiovasc Res, May 1, 2005; 66(2): 213 - 221. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. P. Brandes, I. Fleming, and R. Busse Endothelial aging Cardiovasc Res, May 1, 2005; 66(2): 286 - 294. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Zaccagnini, C. Gaetano, L. Della Pietra, S. Nanni, A. Grasselli, A. Mangoni, R. Benvenuto, M. Fabrizi, S. Truffa, A. Germani, et al. Telomerase Mediates Vascular Endothelial Growth Factor-dependent Responsiveness in a Rat Model of Hind Limb Ischemia J. Biol. Chem., April 15, 2005; 280(15): 14790 - 14798. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Armstrong, G. Saretzki, H. Peters, I. Wappler, J. Evans, N. Hole, T. von Zglinicki, and M. Lako Overexpression of Telomerase Confers Growth Advantage, Stress Resistance, and Enhanced Differentiation of ESCs Toward the Hematopoietic Lineage Stem Cells, April 1, 2005; 23(4): 516 - 529. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Murasawa and T. Asahara Endothelial Progenitor Cells for Vasculogenesis Physiology, February 1, 2005; 20(1): 36 - 42. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-H. Choi, J. Hur, C.-H. Yoon, J.-H. Kim, C.-S. Lee, S.-W. Youn, I.-Y. Oh, C. Skurk, T. Murohara, Y.-B. Park, et al. Augmentation of Therapeutic Angiogenesis Using Genetically Modified Human Endothelial Progenitor Cells with Altered Glycogen Synthase Kinase-3{beta} Activity J. Biol. Chem., November 19, 2004; 279(47): 49430 - 49438. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Xu, J. Jiang, V. Sottile, J. McWhir, J. Lebkowski, and M. K. Carpenter Immortalized Fibroblast-Like Cells Derived from Human Embryonic Stem Cells Support Undifferentiated Cell Growth Stem Cells, November 1, 2004; 22(6): 972 - 980. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Ingram, L. E. Mead, H. Tanaka, V. Meade, A. Fenoglio, K. Mortell, K. Pollok, M. J. Ferkowicz, D. Gilley, and M. C. Yoder Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood Blood, November 1, 2004; 104(9): 2752 - 2760. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Kong, L. G. Melo, M. Gnecchi, L. Zhang, G. Mostoslavsky, C. C. Liew, R. E. Pratt, and V. J. Dzau Cytokine-Induced Mobilization of Circulating Endothelial Progenitor Cells Enhances Repair of Injured Arteries Circulation, October 5, 2004; 110(14): 2039 - 2046. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. G. Melo, M. Gnecchi, A. S. Pachori, D. Kong, K. Wang, X. Liu, R. E. Pratt, and V. J. Dzau Endothelium-Targeted Gene and Cell-Based Therapies for Cardiovascular Disease Arterioscler. Thromb. Vasc. Biol., October 1, 2004; 24(10): 1761 - 1774. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. W. Losordo and S. Dimmeler Therapeutic Angiogenesis and Vasculogenesis for Ischemic Disease: Part II: Cell-Based Therapies Circulation, June 8, 2004; 109(22): 2692 - 2697. [Full Text] [PDF]
|
|
|
|
|
|
J. Haendeler, J. Hoffmann, J. F. Diehl, M. Vasa, I. Spyridopoulos, A. M. Zeiher, and S. Dimmeler Antioxidants Inhibit Nuclear Export of Telomerase Reverse Transcriptase and Delay Replicative Senescence of Endothelial Cells Circ. Res., April 2, 2004; 94(6): 768 - 775. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Serrano and V. Andres Telomeres and Cardiovascular Disease: Does Size Matter? Circ. Res., March 19, 2004; 94(5): 575 - 584. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Hur, C.-H. Yoon, H.-S. Kim, J.-H. Choi, H.-J. Kang, K.-K. Hwang, B.-H. Oh, M.-M. Lee, and Y.-B. Park Characterization of Two Types of Endothelial Progenitor Cells and Their Different Contributions to Neovasculogenesis Arterioscler. Thromb. Vasc. Biol., February 1, 2004; 24(2): 288 - 293. [Abstract] [Full Text]
|
|
|
|
 |
|
 S. Dimmeler and M. Vasa-Nicotera Aging of progenitor cells: limitation for regenerative capacity? J. Am. Coll. Cardiol., December 17, 2003; 42(12): 2081 - 2082. [Full Text] [PDF]
|
|
|
|
|
|
R. Gulati, D. Jevremovic, T. E. Peterson, S. Chatterjee, V. Shah, R. G. Vile, and R. D. Simari Diverse Origin and Function of Cells With Endothelial Phenotype Obtained From Adult Human Blood Circ. Res., November 28, 2003; 93(11): 1023 - 1025. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. E. Szmitko, P. W.M. Fedak, R. D. Weisel, D. J. Stewart, M. J.B. Kutryk, and S. Verma Endothelial Progenitor Cells: New Hope for a Broken Heart Circulation, June 24, 2003; 107(24): 3093 - 3100. [Full Text] [PDF]
|
|