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Innovation in Basic Science: Stem Cells and their role in the treatment of Paediatric Cardiac Failure – Opportunities and Challenges

Published online by Cambridge University Press:  01 November 2009

Sunjay Kaushal ,
Jeffrey Phillip Jacobs ,
Jeffrey G. Gossett ,
Ann Steele ,
Peter Steele ,
Craig R. Davis ,
Elfriede Pahl ,
Kalpana Vijayan ,
Alfred Asante-Korang  and
Robert J. Boucek
...Show all authors
Sunjay Kaushal*
Affiliation:
Divisions of Cardiovascular-Thoracic Surgery, Children’s Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
Jeffrey Phillip Jacobs
Affiliation:
The Congenital Heart Institute of Florida (CHIF), Division of Thoracic and Cardiovascular Surgery, All Children’s Hospital and Children’s Hospital of Tampa, University of South Florida College of Medicine, Cardiac Surgical Associates of Florida (CSAoF), Saint Petersburg and Tampa, Florida, United States of America
Jeffrey G. Gossett
Affiliation:
Division of Cardiology, Children’s Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
Ann Steele
Affiliation:
The Congenital Heart Institute of Florida (CHIF), All Children’s Hospital, Saint Petersburg, Florida, United States of America
Peter Steele
Affiliation:
The Congenital Heart Institute of Florida (CHIF), All Children’s Hospital, Saint Petersburg, Florida, United States of America
Craig R. Davis
Affiliation:
Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children’s Hospital and Department of Pediatrics, The Ohio State University, Columbus, Ohio, United States of America
Elfriede Pahl
Affiliation:
Division of Cardiology, Children’s Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
Kalpana Vijayan
Affiliation:
Divisions of Cardiovascular-Thoracic Surgery, Children’s Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
Alfred Asante-Korang
Affiliation:
The Congenital Heart Institute of Florida (CHIF), Division of Pediatric Cardiology, All Children’s Hospital and Children’s Hospital of Tampa, Saint Petersburg and Tampa, Florida, United States of America
Robert J. Boucek
Affiliation:
Seattle Children’s Hospital and the University of Washington, Seattle, Washington, United States of America
Carl L. Backer
Affiliation:
Divisions of Cardiovascular-Thoracic Surgery, Children’s Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
Loren E. Wold
Affiliation:
Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children’s Hospital and Department of Pediatrics, The Ohio State University, Columbus, Ohio, United States of America
*
Correspondence to: Dr Kaushal, PhD, MD, Division of Cardiovascular-Thoracic Surgery, Children’s Memorial Hospital, 2300 Children’s Plaza, mc 22, Chicago, Illinois, United States of America. Tel: 773-880-4378; Fax: 773-880-3054; E-mail: [email protected]
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Abstract

Heart failure is a leading cause of death worldwide. Current therapies only delay progression of the cardiac disease or replace the diseased heart with cardiac transplantation. Stem cells represent a recently discovered novel approach to the treatment of cardiac failure that may facilitate the replacement of diseased cardiac tissue and subsequently lead to improved cardiac function and cardiac regeneration.

A stem cell is defined as a cell with the properties of being clonogenic, self-renewing, and multipotent. In response to intercellular signalling or environmental stimuli, stem cells differentiate into cells derived from any of the three primary germ layers: ectoderm, endoderm, and mesoderm, a powerful advantage for regenerative therapies. Meanwhile, a cardiac progenitor cell is a multipotent cell that can differentiate into cells of any of the cardiac lineages, including endothelial cells and cardiomyocytes.

Stem cells can be classified into three categories: (1) adult stem cells, (2) embryonic stem cells, and (3) induced pluripotential cells. Adult stem cells have been identified in numerous organs and tissues in adults, including bone-marrow, skeletal muscle, adipose tissue, and, as was recently discovered, the heart. Embryonic stem cells are derived from the inner cell mass of the blastocyst stage of the developing embryo. Finally through transcriptional reprogramming, somatic cells, such as fibroblasts, can be converted into induced pluripotential cells that resemble embryonic stem cells.

Four classes of stem cells that may lead to cardiac regeneration are: (1) Embryonic stem cells, (2) Bone Marrow derived stem cells, (3) Skeletal myoblasts, and (4) Cardiac stem cells and cardiac progenitor cells. Embryonic stem cells are problematic because of several reasons: (1) the formation of teratomas, (2) potential immunologic cellular rejection, (3) low efficiency of their differentiation into cardiomyocytes, typically 1% in culture, and (4) ethical and political issues. As of now, bone marrow derived stem cells have not been proven to differentiate reproducibly and reliably into cardiomyocytes. Skeletal myoblasts have created in vivo myotubes but have not electrically integrated with the myocardium. Cardiac stem cells and cardiac progenitor cells represent one of the most promising types of cellular therapy for children with cardiac failure.

Keywords

Stem cellpaediatricsheart failureembryonic stem cellbone marrow
Type
Original Article
Information
Cardiology in the Young , Volume 19 , Issue S2: Innovation associated with the treatment of patients with congenital and pediatric cardiac disease , November 2009 , pp. 74 - 84
Copyright
Copyright © Cambridge University Press 2009

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References

1.Rosamond, W, Flegal, K, Friday, G, et al. A Report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007; 115: e69–e171.CrossRefGoogle ScholarPubMed
2.Towbin, JA, Lowe, AM, Colan, SD, et al. Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA 2006; 296: 1867–1876.CrossRefGoogle ScholarPubMed
3.Ward, KM, Binns, H, Chin, C, Webber, SA, Canter, CE, Pahl, E. Pediatric heart transplantation for anthracycline cardiomyopathy: cancer recurrence is rare. J Heart Lung Transplant 2004; 23: 1040–1045.CrossRefGoogle ScholarPubMed
4.Rosenthal, D, Chrisant, MRK, Edens, E, et al. International Society or Heart and Lung Transplantation: Practice guidelines for management of heart failure in children. J Heart Lung Transplant 2004; 23 (12): 1313–1333.CrossRefGoogle ScholarPubMed
5.Hunt, SA, Abraham, WT, Chin, MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): Developed in Collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation. Circulation 2005; 112: e154–e235; Epub 2005 Sep 13.Google Scholar
6.Harmon, WG, Sleeper, LA, Cuniberti, L, et al. Treating Children With Idiopathic Dilated Cardiomyopathy (from the Pediatric Cardiomyopathy Registry). Am J Cardiol 2009; 104: 281–286.CrossRefGoogle ScholarPubMed
7.Zannad, F, Alla, F, Dousset, B, Perez, A, Pitt, B. Limitation of Excessive Extracellular Matrix Turnover May Contribute to Survival Benefit of Spironolactone Therapy in Patients With Congestive Heart Failure: Insights From the Randomized Aldactone Evaluation Study (RALES). Circulation 2000; 102: 2700–2706.CrossRefGoogle ScholarPubMed
8.Pitt, B, Zannad, F, Remme, WJ, et al. The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure. N Engl J Med 1999; 341: 709–717.CrossRefGoogle ScholarPubMed
9.Momma, K. ACE Inhibitors in Pediatric Patients with Heart Failure. Paediatr Drugs 2006; 8: 55–69.CrossRefGoogle ScholarPubMed
10.Khalil, ME, Basher, AW, Brown, EJ, Alhaddad, IA. A remarkable medical story: benefits of angiotensin-converting enzyme inhibitors in cardiac patients. J Am Coll Cardiol 2001; 37: 1757–1764.CrossRefGoogle ScholarPubMed
11.Lewis, A, Chabot, M. The Effect of Treatment with Angiotensin-Converting Enzyme Inhibitors on Survival of Pediatric Patients with Dilated Cardiomyopathy. Pediatr Cardiol 1993; 14: 9–12.CrossRefGoogle ScholarPubMed
12.Rahko, PS. An Echocardiographic Analysis of the Long-Term Effects of Carvedilol on Left Ventricular Remodeling, Systolic Performance, and Ventricular Filling Patterns in Dilated Cardiomyopathy. Echocardiography 2005; 22 (7): 547–554.CrossRefGoogle ScholarPubMed
13.Okafor, C, Perreault-Micale, C, Hajjar, R, et al. Chronic treatment with Carvedilol improves ventricular function and reduces myocyte apoptosis in an animal model of heart failure. BMC Physiol 2003; 21 (3): 6 Epub 2003 Jul 21.CrossRefGoogle Scholar
14.Rossig, L, Haendeler, J, Mallat, Z, et al. Congestive Heart Failure Induces Endothelial Cell Apoptosis: Protective Role of Carvedilol. J Am Coll Cardiol 2000; 36: 2081–2089.CrossRefGoogle ScholarPubMed
15.Shaddy, RE, Boucek, MM, Hsu, DT, et al. Carvedilol for Children and Adolescents With Heart Failure: A Randomized Controlled Trial. JAMA 2007; 298: 1171–1179.CrossRefGoogle ScholarPubMed
16.Imamura, M, Dossey, AM, Prodhan, P, et al. Bridge to Cardiac Transplant in Children: Berlin Heart versus Extracorporeal Membrane Oxygenation. Ann Thorac Surg 2009; 87: 1894–1901.CrossRefGoogle ScholarPubMed
17.Hetzer, R, Potapov, EV, Stiller, B, et al. Improvement in Survival after Mechanical Circulatory Support with Pneumatic Pulsatile Ventricular Assist Devices in Pediatric Patients. Ann Thorac Surg 2006; 82: 917–925.CrossRefGoogle ScholarPubMed
18.Blume, ED, Naftel, DC, Bastardi, HJ, et al. Outcomes of Children Bridged to Heart Transplantation with Ventricular Assist Devices: A Multi-Institutional Study. Circulation 2006; 113: 2313–2319.CrossRefGoogle ScholarPubMed
19.Cecchin, F, Frangini, PA, Brown, DW, et al. Cardiac Resynchronization Therapy (and Multisite Pacing) in Pediatrics and Congenital Heart Disease: Five Years Experience in a Single Institution. J Cardiovasc Electrophysiol 2009; 20: 58–65; Epub 2008 Sep.CrossRefGoogle Scholar
20.Boucek, MM, Aurora, P, Edwards, LB, Taylor, DO, Trulock, EP, Christie, J, Dobbels, F, Rahmel, AO, Keck, BM, Hertz, MI. Registry of the International Society for Heart and Lung Transplantation: tenth official paediatric heart transplantation report – 2007. J Heart Lung Transplant 2007; 26: 796–807.CrossRefGoogle ScholarPubMed
21.Lamour, JM, Kanter, KR, Naftel, DC, et al. Cardiac Transplant Registry Database; Pediatric Heart Transplant Study. The effect of age, diagnosis, and previous surgery in children and adults undergoing heart transplantation for congenital heart disease. J Am Coll Cardiol 2009; 54: 160–165.CrossRefGoogle Scholar
22.Beltrami, AP, Barlucci, L, Torella, D, et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003; 114: 763–776.CrossRefGoogle ScholarPubMed
23.Steele, A, Jones, OY, Gok, F, et al. Stem-like cells traffic from heart ex vivo, expand in vitro, and can be transplanted in vivo. JHLT 2005; 24 (11): 1930–1939.Google ScholarPubMed
24.Oh, H, Bradfute, SB, Gallardo, TD, et al. Cardiac progenitor cells from adult myocardium: homing differentiation and fusion after infarction. Proc Natl Acad Sci USA 2003; 100 (21): 12313–12318.CrossRefGoogle ScholarPubMed
25.Messina, E, De Angelis, L, Frati, G, et al. Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ Res 2004; 95: 911–921.CrossRefGoogle ScholarPubMed
26.Martin, CM, Meeson, AP, Robertson, SM, et al. Persistent Expression of the ATP-Binding Cassette Transporter Abeg2 Identifies Cardiac SP Cells in the Developing Adult Heart. Dev Biol 2004; 265: 262–275.CrossRefGoogle ScholarPubMed
27.Pfister, O, Mouquet, F, Jain, M, et al. CD31- But Not CD31+ Cardiac Side Population Cells Exhibit Functional Cardiomyogenic Differentiation. Circ Res 2005; 97: 52–61.CrossRefGoogle ScholarPubMed
28.Laugwitz, KL, Moretti, A, Lam, J, et al. Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 2005; 433: 647–653.CrossRefGoogle ScholarPubMed
29.Urbanek, K, Quaini, F, Tasca, G, et al. Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy. Pro Natl Acad Sci U S A 2003; 100: 10440–10445.CrossRefGoogle ScholarPubMed
30.Quaini, F, Urbanek, K, Beltrami, AP, et al. Chimerism of the transplanted heart. N Engl J Med 2002; 346: 5–15.CrossRefGoogle ScholarPubMed
31.Muller, P, Pfeiffer, P, Koglin, J, et al. Cardiomyocytes of noncardiac origin in myocardial biopsies of human transplanted hearts. Circulation 2002; 106: 31–35.CrossRefGoogle ScholarPubMed
32.Laflamme, MA, Murry, CE. Regenerating the heart. Nat Biotechnol 2005; 23: 845–956.CrossRefGoogle ScholarPubMed
33.Yamanaka, S. A fresh look at iPS Cells. Cell 2009; 137: 13–17.CrossRefGoogle Scholar
34.Sánchez, PL, Villa, A, Sanz, R, et al. Present and future of stem cells for cardiovascular therapy. Ann Med 2007; 39: 412–427.CrossRefGoogle ScholarPubMed
35.Boudoulos, KD, Hatzopoulos, AK. Cardiac repair and regeneration: the Rubik’s cube of cell therapy for heart disease. Dis Mod Mech 2009; 2: 344–358.CrossRefGoogle Scholar
36.Angert, D, Houser, SR. Stem cell therapy for heart failure. Curr Treat Opt Cardiovasc Med 2009; 11: 316–327.CrossRefGoogle ScholarPubMed
37.Freund, C, Mummery, CL. Prospects for pluripotent stem cell-derived cardiomyocytes in cardiac cell therapy and as disease models. J Cell Biochem 2009; 107: 592–599.CrossRefGoogle ScholarPubMed
38.Quaini, F, Urbanek, K, Beltrami, AP, et al. Chimerism of the transplanted heart. N Engl J Med 2002; 346: 5–15.CrossRefGoogle ScholarPubMed
39.Bergmann, O, Bhardwaj, RD, Bernard, S, et al. Evidence for cardiomyocyte renewal in humans. Science 2009; 324: 98–102.CrossRefGoogle ScholarPubMed
40.Dill, T, Schächinger, V, Rolf, A, et al. Intracoronary administration of bone marrow-derived progenitor cells improves left ventricular function in patients at risk for adverse remodeling after acute ST-segment elevation myocardial infarction: results of the Reinfusion of Enriched Progenitor cells And Infarct Remodeling in Acute Myocardial Infarction study (REPAIR-AMI) cardiac magnetic resonance imaging substudy. Am Heart J 2009; 157: 541–547.CrossRefGoogle ScholarPubMed
41.Schächinger, V, Erbs, S, Elsässer, A, et al. REPAIR-AMI Investigators clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial. Eur Heart J 2006; 27: 2775–2783.CrossRefGoogle ScholarPubMed
42.Meyer, GP, Wollert, KC, Lotz, J, et al. Intracoronary bone marrow cell transfer after myocardial infarction; eighteen months follow-up data from the randomized, controlled BOOST (Bone marrOw transfer to enhance ST-elevation infarct regeneration) trial. Circlation 2006; 113: 1287–1294.CrossRefGoogle ScholarPubMed
43.Toma, C, Pittenger, MF, Cahill, KS, Byrne, BJ, Kessler, PD. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 2002; 105: 93–98.CrossRefGoogle ScholarPubMed
44.Barile, L, Messina, E, Giacomello, A, Marban, E. Endogenous cardiac stem cells. Prog Cardiovasc Dis 2007; 50: 31–48.CrossRefGoogle ScholarPubMed
45.Steele, A, Steele, P. Stem cells for repair of the heart. Curr Opin Pediatr 2006; 18 (5): 518–523; Review.CrossRefGoogle ScholarPubMed
46.Deglurkar, I, Mal, N, Mills, WR, et al. Mechanical and electrical effects of cell-based gene therapy for ischemic cardiomyopathy are independent. Hum Gene Ther 2006; 17: 1144–1151.CrossRefGoogle ScholarPubMed
47.Menasche, P, Alferi, O, Janssens, S, et al. The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation 2008; 117: 1189–1200.CrossRefGoogle ScholarPubMed
48. MG Biotherapeutics: News: Genzyme ends enrollment in phase 2 trial of cardiac cell therapy. Available at http://www.mgbiotherapeutics.com/uscorp/news/mgb_en_p_ci_news_MAGIC.asp. Accessed February 2009.Google Scholar
49.Yamanaka, S. A fresh look at iPS cells. Cell 2009; 137: 13–17.CrossRefGoogle Scholar
50.Mauritz, C, Schwanke, K, Reppel, M, Neef, S, Katsirntaki, K, Maier, LS, Nguemo, F, Menke, S, Haustein, M, Hescheler, J, Hasenfuss, G, Martin, U. Generation of functional murine cardiomyocytes from induced pluripotent cells. Circulation 2008; 118: 507–517.CrossRefGoogle Scholar
51.Wold, LE, Dai, W, Sesti, C, et al. Stem Cell Therapy for the Heart. CHF 2004; 10 (6): 293–301.Google ScholarPubMed
52.Dimmeler, S, Seiher, AM, Schneider, MD. Unchain my heart: the scientific foundation of cardiac repair. J Clin Invest 2005; 115 (3): 572–583.CrossRefGoogle ScholarPubMed
53.Aicher, A, Brenner, W, Zyhayra, M, et al. Assessment of the tissue distribution of transplanted human endothelial progenitor cells by radioactive labeling. Circulation 2003; 107: 2134–2139.CrossRefGoogle ScholarPubMed
54.Poss, KD, Wilson, LG, Keating, MT. Heart regeneration in zebrafish. Science 2002; 298: 2188–2190.CrossRefGoogle ScholarPubMed
55.Kaushal, S, Amiel, GE, Guleserian, KJ, et al. Functional small-diameter neovessels created using endothelial progenitor cells expanded ex vivo. Nat Med 2001; 7 (9): 1035–1040.CrossRefGoogle ScholarPubMed
56.Sutherland, FW, Perry, TE, Yu, Y, et al. From Stem cells to viable autologous semilunar heart valve. Circulation 2005; 111: 2783–2791.CrossRefGoogle ScholarPubMed
57.Neuenschwander, S, Hoerstrup, SP. Heart valve tissue engineering. Transpl Immunol 2004; 12: 359–365.CrossRefGoogle ScholarPubMed
58.Hoenig, MR, Campbell, GR, Rolfe, BE, Campbell, JH. Tissue-engineered blood vessels: alternative to autologous grafts? Arterioscler Thromb Vasc Biol 2005; 25: 1128–1134.CrossRefGoogle ScholarPubMed
59.Sales, KM, Salacinski, HJ, Alobaid, N, et al. Advancing vascular tissue engineering: the role of stem cell technology. Trends Biotechnol 2005; 23: 461–467.CrossRefGoogle ScholarPubMed