Published online before print June 30, 2003, doi: 10.1161/01.CIR.0000079161.56080.22
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2003;108:889.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Hybrid Cell–Gene Therapy for Pulmonary Hypertension Based on Phagocytosing Action of Endothelial Progenitor Cells
From the Departments of Internal Medicine (N.N., T.H., K.M.) and Perinatology (Y.C.), National Cardiovascular Center, Osaka, Japan; Departments of Biochemistry (K.K., J.H., M.H.-S., H.O.), Cardiac Physiology (M.K., H.M.), and Structural Analysis (N.M.), National Cardiovascular Center Research Institute, Osaka, Japan; Cardiovascular Division (M.U.), Kansai Rosai Hospital, Hyogo, Japan; Department of Physiology (N.F.), Tokai University School of Medicine, Kanagawa, Japan; Department of Biomaterials (Y.T.), Field of Tissue Engineering, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan; Department of Transfusion Medicine (K.N., H.H.), Hyogo College of Medicine, Hyogo, Japan; and Department of Regenerative Medicine (T.A.), Institute of Biomedical Research and Innovation, Kobe, Japan.
Reprint requests to Noritoshi Nagaya, MD, or Hidezo Mori, MD, Department of Internal Medicine, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. E-mail nagayann{at}hsp.ncvc.go.jp or hidemori@ri.ncvc.go.jp
Received December 3, 2002; revision received April 17, 2003; accepted April 18, 2003.
Background— Circulating endothelial progenitor cells (EPCs) migrate to injured vascular endothelium and differentiate into mature endothelial cells. We investigated whether transplantation of vasodilator gene-transduced EPCs ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats.
Methods and Results— We obtained EPCs from cultured human umbilical cord blood mononuclear cells and constructed plasmid DNA of adrenomedullin (AM), a potent vasodilator peptide. We used cationic gelatin to produce ionically linked DNA-gelatin complexes. Interestingly, EPCs phagocytosed plasmid DNA-gelatin complexes, which allowed nonviral, highly efficient gene transfer into EPCs. Intravenously administered EPCs were incorporated into the pulmonary vasculature of immunodeficient nude rats given MCT. Transplantation of EPCs alone modestly attenuated MCT-induced pulmonary hypertension (16% decrease in pulmonary vascular resistance). Furthermore, transplantation of AM DNA-transduced EPCs markedly ameliorated pulmonary hypertension in MCT rats (39% decrease in pulmonary vascular resistance). MCT rats transplanted with AM-expressing EPCs had a significantly higher survival rate than those given culture medium or EPCs alone.
Conclusions— Umbilical cord blood–derived EPCs had a phagocytosing action that allowed nonviral, highly efficient gene transfer into EPCs. Transplantation of AM gene-transduced EPCs caused significantly greater improvement in pulmonary hypertension in MCT rats than transplantation of EPCs alone. Thus, a novel hybrid cell–gene therapy based on the phagocytosing action of EPCs may be a new therapeutic strategy for the treatment of pulmonary hypertension.
Key Words: pulmonary heart disease • natriuretic peptides • gene therapy • endothelium
This article has been cited by other articles:
 |
|
 |
|
  S. Umar, Y. P. de Visser, P. Steendijk, C. I. Schutte, E. H. Laghmani, G. T. M. Wagenaar, W. H. Bax, E. Mantikou, D. A. Pijnappels, D. E. Atsma, et al. Allogenic stem cell therapy improves right ventricular function by improving lung pathology in rats with pulmonary hypertension Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1606 - H1616. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J H W Distler, Y Allanore, J Avouac, R Giacomelli, S Guiducci, F Moritz, A Akhmetshina, U A Walker, A Gabrielli, U Muller-Ladner, et al. EULAR Scleroderma Trials and Research group statement and recommendations on endothelial precursor cells Ann Rheum Dis, February 1, 2009; 68(2): 163 - 168. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Satoh, Y. Fukumoto, M. Nakano, K. Sugimura, J. Nawata, J. Demachi, A. Karibe, Y. Kagaya, N. Ishii, K. Sugamura, et al. Statin ameliorates hypoxia-induced pulmonary hypertension associated with down-regulated stromal cell-derived factor-1 Cardiovasc Res, January 1, 2009; 81(1): 226 - 234. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Weiss, J. K. Kolls, L. A. Ortiz, A. Panoskaltsis-Mortari, and D. J. Prockop Stem Cells and Cell Therapies in Lung Biology and Lung Diseases Proceedings of the ATS, July 15, 2008; 5(5): 637 - 667. [Full Text] [PDF]
|
|
|
|
 |
|
 G.-P. Diller, S. van Eijl, D. O. Okonko, L. S. Howard, O. Ali, T. Thum, S. J. Wort, E. Bedard, J. S. R. Gibbs, J. Bauersachs, et al. Circulating Endothelial Progenitor Cells in Patients With Eisenmenger Syndrome and Idiopathic Pulmonary Arterial Hypertension Circulation, June 10, 2008; 117(23): 3020 - 3030. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Spees, M. J. Whitney, D. E. Sullivan, J. A. Lasky, M. Laboy, J. Ylostalo, and D. J. Prockop Bone marrow progenitor cells contribute to repair and remodeling of the lung and heart in a rat model of progressive pulmonary hypertension FASEB J, April 1, 2008; 22(4): 1226 - 1236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Satoh and B. C. Berk Circulating smooth muscle progenitor cells: novel players in plaque stability Cardiovasc Res, February 1, 2008; 77(3): 445 - 447. [Full Text] [PDF]
|
|
|
|
 |
|
 X.-X. Wang, F.-R. Zhang, Y.-P. Shang, J.-H. Zhu, X.-D. Xie, Q.-M. Tao, J.-H. Zhu, and J.-Z. Chen Transplantation of Autologous Endothelial Progenitor Cells May Be Beneficial in Patients With Idiopathic Pulmonary Arterial Hypertension: A Pilot Randomized Controlled Trial J. Am. Coll. Cardiol., April 10, 2007; 49(14): 1566 - 1571. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sahara, M. Sata, T. Morita, K. Nakamura, Y. Hirata, and R. Nagai Diverse Contribution of Bone Marrow Derived Cells to Vascular Remodeling Associated With Pulmonary Arterial Hypertension and Arterial Neointimal Formation Circulation, January 30, 2007; 115(4): 509 - 517. [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]
|
|
|
|
 |
|
 T. Marumo, H. Uchimura, M. Hayashi, K. Hishikawa, and T. Fujita Aldosterone Impairs Bone Marrow-Derived Progenitor Cell Formation Hypertension, September 1, 2006; 48(3): 490 - 496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. C.H. Hsieh, C. MacGillivray, J. Gannon;, F. U. Cruz, and R. T. Lee Local Controlled Intramyocardial Delivery of Platelet-Derived Growth Factor Improves Postinfarction Ventricular Function Without Pulmonary Toxicity Circulation, August 15, 2006; 114(7): 637 - 644. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. D. Zhao, D. W. Courtman, D. S. Ng, M. J. Robb, Y. P. Deng, J. Trogadis, R. N. N. Han, and D. J. Stewart Microvascular Regeneration in Established Pulmonary Hypertension by Angiogenic Gene Transfer Am. J. Respir. Cell Mol. Biol., August 1, 2006; 35(2): 182 - 189. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kanki-Horimoto, H. Horimoto, S. Mieno, K. Kishida, F. Watanabe, E. Furuya, and T. Katsumata Implantation of Mesenchymal Stem Cells Overexpressing Endothelial Nitric Oxide Synthase Improves Right Ventricular Impairments Caused by Pulmonary Hypertension Circulation, July 4, 2006; 114(1_suppl): I-181 - I-185. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sata Role of Circulating Vascular Progenitors in Angiogenesis, Vascular Healing, and Pulmonary Hypertension: Lessons From Animal Models Arterioscler Thromb Vasc Biol, May 1, 2006; 26(5): 1008 - 1014. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Satoh, Y. Kagaya, M. Nakano, Y. Ito, J. Ohta, H. Tada, A. Karibe, N. Minegishi, N. Suzuki, M. Yamamoto, et al. Important Role of Endogenous Erythropoietin System in Recruitment of Endothelial Progenitor Cells in Hypoxia-Induced Pulmonary Hypertension in Mice Circulation, March 21, 2006; 113(11): 1442 - 1450. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kataoka, N. Nagaya, T. Satoh, T. Itoh, S. Murakami, T. Iwase, Y. Miyahara, S. Kyotani, Y. Sakai, K. Kangawa, et al. A Long-Acting Prostacyclin Agonist with Thromboxane Inhibitory Activity for Pulmonary Hypertension Am. J. Respir. Crit. Care Med., December 15, 2005; 172(12): 1575 - 1580. [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]
|
|
|
|
 |
|
 N. Nagaya, H. Mori, S. Murakami, K. Kangawa, and S. Kitamura Adrenomedullin: angiogenesis and gene therapy Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2005; 288(6): R1432 - R1437. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Uchimura, T. Marumo, O. Takase, H. Kawachi, F. Shimizu, M. Hayashi, T. Saruta, K. Hishikawa, and T. Fujita Intrarenal Injection of Bone Marrow-Derived Angiogenic Cells Reduces Endothelial Injury and Mesangial Cell Activation in Experimental Glomerulonephritis J. Am. Soc. Nephrol., April 1, 2005; 16(4): 997 - 1004. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. D. Zhao, D. W. Courtman, Y. Deng, L. Kugathasan, Q. Zhang, and D. J. Stewart Rescue of Monocrotaline-Induced Pulmonary Arterial Hypertension Using Bone Marrow-Derived Endothelial-Like Progenitor Cells: Efficacy of Combined Cell and eNOS Gene Therapy in Established Disease Circ. Res., March 4, 2005; 96(4): 442 - 450. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Iwase, N. Nagaya, T. Fujii, T. Itoh, H. Ishibashi-Ueda, M. Yamagishi, K. Miyatake, T. Matsumoto, S. Kitamura, and K. Kangawa Adrenomedullin Enhances Angiogenic Potency of Bone Marrow Transplantation in a Rat Model of Hindlimb Ischemia Circulation, January 25, 2005; 111(3): 356 - 362. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Itoh, N. Nagaya, S. Murakami, T. Fujii, T. Iwase, H. Ishibashi-Ueda, C. Yutani, M. Yamagishi, H. Kimura, and K. Kangawa C-type Natriuretic Peptide Ameliorates Monocrotaline-induced Pulmonary Hypertension in Rats Am. J. Respir. Crit. Care Med., December 1, 2004; 170(11): 1204 - 1211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hristov, W. Erl, S. Linder, and P. C. Weber Apoptotic bodies from endothelial cells enhance the number and initiate the differentiation of human endothelial progenitor cells in vitro Blood, November 1, 2004; 104(9): 2761 - 2766. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Matsui, T. Shimosawa, K. Itakura, X. Guanqun, K. Ando, and T. Fujita Adrenomedullin Can Protect Against Pulmonary Vascular Remodeling Induced by Hypoxia Circulation, May 11, 2004; 109(18): 2246 - 2251. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Stewart, Y. D. Zhao, D. W. Courtman, N. Nagaya, T. Horio, K. Miyatake, Y. Chiba, K. Kangawa, M. Kanda, J. Hino, et al. Cell Therapy for Pulmonary Hypertension: What Is the True Potential of Endothelial Progenitor Cells? * Response Circulation, March 30, 2004; 109(12): e172 - e173. [Full Text] [PDF]
|
|
|
|
|
|
N. Tokunaga, N. Nagaya, M. Shirai, E. Tanaka, H. Ishibashi-Ueda, M. Harada-Shiba, M. Kanda, T. Ito, W. Shimizu, Y. Tabata, et al. Adrenomedullin Gene Transfer Induces Therapeutic Angiogenesis in a Rabbit Model of Chronic Hind Limb Ischemia: Benefits of a Novel Nonviral Vector, Gelatin Circulation, February 3, 2004; 109(4): 526 - 531. [Abstract] [Full Text] [PDF]
|
|