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Application of Mesenchymal Stem Cell-Derived Cardiomyocytes as Bio-pacemakers: Current Status and Problems to Be Solved

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Biopacemaking

Part of the book series: Series in Biomedical Engineering ((BIOMENG))

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Abstract

Bone marrow mesenchymal stem cells (CMG cells) are multipotent and can be induced by 5-azacytidine to differentiate into cardiomyocytes. We characterized the electrophysiological properties of these cardiomyocytes and investigated their potential for use as transplantable bio-pacemakers. After differentiation, action potentials in spontaneously beating cardiomyocytes were initially sinus node-like, but subsequently became ventricular cardiomyocyte-like. RT-PCR established that ion channels mediating I K1 and I Kr were expressed before differentiation. After differentiation, ion channels underlying I Ca,L and I f were expressed first, followed by ion channels mediating I to and I K,ATP. Differentiated CMG cells expressed β-adrenergic receptors and increased their beat rate in response to isoproterenol. CMG cardiomyocytes were purified using GFP fluorescence and transplanted into the free walls of the left ventricles of mice. The transplanted cardiomyocytes survived and connected to surrounding recipient cardiomyocytes via intercalated discs. Although further innovation is required, the present findings provide evidence of the potential for bone marrow-derived cardiomyocytes to be used as bio-pacemakers.

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References

  1. Amado LC et al (2005) Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc Natl Acad Sci USA 102:11474–11479

    Article  Google Scholar 

  2. Ashton BA et al (1980) Formation of bone and cartilage by marrow stromal cells in diffusion chambers in vivo. Clin Orthop Relat Res 151:294–307

    Google Scholar 

  3. Boheler KR et al (2002) Differentiation of pluripotent embryonic stem cells into cardiomyocytes. Circ Res 91:189–201

    Article  Google Scholar 

  4. Brillantes AM, Bezprozvannaya S, Marks AR (1994) Developmental and tissue-specific regulation of rabbit skeletal and cardiac muscle calcium channels involved in excitation-contraction coupling. Circ Res 75:503–510

    Google Scholar 

  5. Choate JK, Feldman R (2003) Neuronal control of heart rate in isolated mouse atria. Am J Physiol Heart Circ Physiol 285:H1340–H1346

    Google Scholar 

  6. Choi YH et al (2006) Cardiac conduction through engineered tissue. Am J Pathol 169: 72–85

    Article  Google Scholar 

  7. Chutkow WA et al (1996) Cloning, tissue expression, and chromosomal localization of SUR2, the putative drug-binding subunit of cardiac, skeletal muscle, and vascular KATP channels. Diabetes 45:1439–1445

    Article  Google Scholar 

  8. Eberhardt F et al (2005) Long term complications in single and dual chamber pacing are influenced by surgical experience and patient morbidity. Heart 91:500–506

    Article  Google Scholar 

  9. Edelberg JM, Aird WC, Rosenberg RD (1998) Enhancement of murine cardiac chronotropy by the molecular transfer of the human beta2 adrenergic receptor cDNA. J Clin Invest 101:337–343

    Google Scholar 

  10. Ferrari G et al (1998) Muscle regeneration by bone marrow-derived myogenic progenitors. Science 279:1528–1530

    Article  Google Scholar 

  11. Friedenstein AJ, Chailakhyan RK, Gerasimov UV (1987) Bone marrow osteogenic stem cells: in vitro cultivation and transplantation in diffusion chambers. Cell Tissue Kinet 20:263–272

    Google Scholar 

  12. Geiser F, Baudinette RV, McMurchie EJ (1989) The effect of temperature on isolated perfused hearts of heterothermic marsupials. Comp Biochem Physiol A 93:331–335

    Article  Google Scholar 

  13. Hakuno D et al (2002) Bone marrow-derived regenerated cardiomyocytes (CMG Cells) express functional adrenergic and muscarinic receptors. Circulation 105:380–386

    Article  Google Scholar 

  14. Hattan N et al (2005) Purified cardiomyocytes from bone marrow mesenchymal stem cells produce stable intracardiac grafts in mice. Cardiovasc Res 65:334–344

    Article  Google Scholar 

  15. Henderson SA et al (1989) Structure, organization, and expression of the rat cardiac myosin light chain-2 gene. Identification of a 250-base pair fragment which confers cardiacspecific expression. J Biol Chem 264:18142–18148

    Google Scholar 

  16. Hidaka K et al (2003) Chamber-specific differentiation of Nkx2.5-positive cardiac precursor cells from murine embryonic stem cells. FASEB J 17:740–742

    Google Scholar 

  17. Hou PC, Burggren WW (1989) Interaction of allometry and development in the mouse Mus musculus: heart rate and hematology. Respir Physiol 78:265–280

    Article  Google Scholar 

  18. Itabashi Y et al (2005) A new method for manufacturing cardiac cell sheets using fibrincoated dishes and its electrophysiological studies by optical mapping. Artif Organs 29:95–103

    Article  Google Scholar 

  19. Kawada H et al (2004) Nonhematopoietic mesenchymal stem cells can be mobilized and differentiate into cardiomyocytes after myocardial infarction. Blood 104:3581–3587

    Article  Google Scholar 

  20. Kehat I et al (2004) Electromechanical integration of cardiomyocytes derived from human embryonic stem cells. Nat Biotechnol 22:1282–1289

    Article  Google Scholar 

  21. Kuratomi S et al (2006) NRSF regulates the developmental and hypertrophic changes of HCN4 transcription in rat cardiac myocytes. Biochem Biophys Res Commun 353:67–73

    Article  Google Scholar 

  22. Kuwahara K et al (2003) NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function. EMBO J 22:6310–6321

    Article  Google Scholar 

  23. Makino S et al (1999) Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest 103:697–705

    Article  Google Scholar 

  24. Maltsev VA et al (1994) Cardiomyocytes differentiated in vitro from embryonic stem cells developmentally express cardiac-specific genes and ionic currents. Circ Res 75:233–244

    Google Scholar 

  25. Muller M et al (2000) Selection of ventricular-like cardiomyocytes from ES cells in vitro. FASEB J 14:2540–2548

    Article  Google Scholar 

  26. O’Brien TX, Lee KJ, Chien KR (1993) Positional specification of ventricular myosin light chain 2 expression in the primitive murine heart tube. Proc Natl Acad Sci USA 90:5157–5161

    Article  Google Scholar 

  27. Rickard DJ et al (1994) Induction of rapid osteoblast differentiation in rat bone marrow stromal cell cultures by dexamethasone and BMP-2. Dev Biol 161:218–228

    Article  Google Scholar 

  28. Rosen MR et al (2004) Recreating the biological pacemaker. Anat Rec A Discov Mol Cell Evol Biol 280:1046–1052

    Article  Google Scholar 

  29. Rozner MA, Burton AW, Kumar A (2005) Pacemaker complication during magnetic resonance imaging. J Am Coll Cardiol 45:161–162 (author reply 162)

    Article  Google Scholar 

  30. Umezawa A et al (1992) Multipotent marrow stromal cell line is able to induce hematopoiesis in vivo. J Cell Physiol 151:197–205

    Article  Google Scholar 

  31. Viswanathan PC et al (2006) Recreatingan artificial biological pacemaker: insights from a theoretical model. Heart Rhythm 3:824–831

    Article  Google Scholar 

  32. Wahler G.M (1992) Developmental increases in the inwardly rectifying potassium current of rat ventricular myocytes. Am J Physiol 262:C1266–C1272

    Google Scholar 

  33. Wei H et al (2005) Embryonic stem cells and cardiomyocyte differentiation: phenotypic and molecular analyses. J Cell Mol Med 9:804–817

    Article  Google Scholar 

  34. Wetzel GT, Klitzner TS (1996) Developmental cardiac electrophysiology recent advances in cellular physiology. Cardiovasc Res 31:E52–E60

    Article  Google Scholar 

  35. Wickenden AD et al (1997) Effects of development and thyroid hormone on K+ currents and K+ channel gene expression in rat ventricle. J Physiol 504:271–286

    Article  Google Scholar 

  36. Xue T et al (2005) Functional integration of electrically active cardiac derivatives from genetically engineered human embryonic stem cells with quiescent recipient ventricular cardiomyocytes: insights into the development of cell-based pacemakers. Circulation 111:11–20

    Article  Google Scholar 

  37. Yasui K et al (2001) I(f) current and spontaneous activity in mouse embryonic ventricular myocytes. Circ Res 88:536–542

    Google Scholar 

  38. Yuasa S et al (2005) Transient inhibition of BMP signaling by Noggin induces cardiomyocyte differentiation of mouse embryonic stem cells. Nat Biotechnol 23:607–611

    Article  Google Scholar 

  39. Zimmermann WH et al (2006) Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts. Nat Med 12:452–458

    Article  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, Institute of Integrated Medical Research, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Yuichi Tomita, Shinji Makino, Daihiko Hakuno, Naoichiro Hattan, Kensuke Kimura, Mitsushige Murata, Masaki Ieda & Keiichi Fukuda

  2. Cardiology Division, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan

    Yuichi Tomita, Daihiko Hakuno, Shunichiro Miyoshi, Mitsushige Murata & Masaki Ieda

Authors
  1. Yuichi Tomita
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  2. Shinji Makino
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  3. Daihiko Hakuno
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  4. Naoichiro Hattan
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  5. Kensuke Kimura
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  6. Shunichiro Miyoshi
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  7. Mitsushige Murata
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  8. Masaki Ieda
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  9. Keiichi Fukuda
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Editor information

Editors and Affiliations

  1. Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

    J. A. E Spaan

  2. Department of Experimental Cardiology, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

    Ruben Coronel

  3. Department of Experimental Cardiology Center for Heart Failure Research, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam

    Jacques M. T. de Bakker

  4. The Heart Lung Center, University Medical Center, Utrecht

    Jacques M. T. de Bakker

  5. The Interuniversity Cardiology, Institute of the Netherlands, Utrecht, The Netherlands

    Jacques M. T. de Bakker

  6. Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Piazza della Scienza 2, 20126, Milano, Italy

    Antonio Zaza

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© 2007 Springer-Verlag Berlin Heidelberg

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Tomita, Y. et al. (2007). Application of Mesenchymal Stem Cell-Derived Cardiomyocytes as Bio-pacemakers: Current Status and Problems to Be Solved. In: Spaan, J.A.E., Coronel, R., de Bakker, J.M.T., Zaza, A. (eds) Biopacemaking. Series in Biomedical Engineering. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-72110-9_10

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  • DOI: https://doi.org/10.1007/978-3-540-72110-9_10

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-540-72109-3

  • Online ISBN: 978-3-540-72110-9

  • eBook Packages: EngineeringEngineering (R0)

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