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Integration of Stem Cells into the Cardiac Syncytium: Formation of Gap Junctions

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Regenerating the Heart

Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

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Abstract

The heart is a functional syncytium. This means that each myocyte is electrically connected to other myocytes in its vicinity. Functional electrical coupling requires gap junctions. Gap junctions are composed of connexins. There are over 20 connexins in the human genome. If either electrical or mechanical regeneration of cardiac function is to be achieved via cell therapy (exclusive of paracrine effects), then the delivery cells must couple to the existing myocytes via gap junctions. In this chapter we review the basic physiology of gap junctions and what is known about their expression in cardiac myocytes and in stem cells. Given that multiple connexins are expressed in myocytes, we consider the types of gap junction channels that can be formed and their prevalence in a calculation of independent assortment of equally expressed connexins. Finally, myocytes are not the only cells present in the heart; there is a substantial presence of fibroblasts and endothelial cells. Fibroblasts do not express the same assortment of connexins as myocytes and do not in general form gap junctions with them. When stem cells are considered for cardiac regeneration, their expression of cardiac connexins is usually confirmed. However, it is just as important to confirm the absence of fibroblast connexins which could potentially create a sink for the local circuit currents that generate the cardiac impulse. Given the excitement generated by induced pluripotent stem cells which are derived from fibroblasts, it will be particularly important to demonstrate that the new myocytes generated from these cells express only cardiac-myocyte-specific connexins.

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References

  1. Harris, A., Emerging issues of connexin channels: biophysics fills the gap. Q. Rev. Biophys. 34:325–472, 2001

    PubMed  CAS  Google Scholar 

  2. Valiunas, V., E.C. Beyer and P.R. Brink Cardiac gap junction channels show a quantitative difference in selectivity. Circ. Res. 91(2):104–111, 2002.

    Article  PubMed  CAS  Google Scholar 

  3. Goldberg, G., Valiunas, V. and Brink, P.R. Selectivity permeability of gap junction channels. Biochem. Biophys. Acta 662: 96–101, 2004.

    Google Scholar 

  4. Brink, P.R., Ramanan, S.V. and Christ, G.J. Human connexin43 gap junction channel gating: evidence for mode shifts and/or heterogeneity. Am. J. Physiol. 271: C321–C331, 1996.

    PubMed  CAS  Google Scholar 

  5. Ek-Vitorin, J.F. and J.M. Burt. Quantification of gap junction selectivity. Am. J. Physiol. Cell Physiol. 289(6): C1535–C1546, 2005.

    Article  PubMed  CAS  Google Scholar 

  6. Kumar, N. Molecular biology of the interactions between connexins. In: Gap junction-mediated intercellular signaling in health and disease. 1999 pages 6–15 Novartis Foundation Symposium 219 Wiley

    Google Scholar 

  7. White, T.W. and R. Bruzzone, Multiple connexin proteins in single intercellular channels: connexin compatibility and functional consequences. J. Bioenerg. Biomembr. 28(4): 339–350, 1996.

    Article  PubMed  CAS  Google Scholar 

  8. Kanaporis, G, G. Mese, L. Valiuniene, T.W. White, P.R. Brink, V. Valiunas. Gap junction channels exhibit connexin-specific permeability to cyclic nucleotides. J. Gen. Physiol. 131: 293–305, 2008

    Article  PubMed  CAS  Google Scholar 

  9. Niessen, H., Harz, H., Bedner, P., Kramer, K., Willecke, K. Selective permeability of different connexin channels to the second messenger IP3. J. Cell Sci. 113: 1365–1372, 2000.

    PubMed  CAS  Google Scholar 

  10. Beyer, E.C. Gap junctions. Int. Rev. Cytol. 137C: 1–37, 1993.

    PubMed  CAS  Google Scholar 

  11. Van Veen, T.A.B., H.W.M. van Rijen and T. Opthof. Cardiac gap junction channels: modulation of expression and channel properties. Cardiovasc. Res. 51: 217–229, 2001.

    Article  PubMed  Google Scholar 

  12. Simpson, I., B. Rose and W.R. Loewenstein Size limit of molecules permeating the junctional membrane channels. Science 195: 294–296, 1977.

    Article  PubMed  CAS  Google Scholar 

  13. Schwarzmann, G., H. Wiegarndt, B. Rose, A. Zimmerman, D. Ben-Haim, W. Loewenstein Diameter of the cell to cell junctional membrane channels as probed with neutral molecules. Science 213: 551–553, 1981.

    Article  PubMed  CAS  Google Scholar 

  14. Neijssen, J. Herberts, C., Drijfhout, J.W., Reits, E., Janssen, L. and Neefjes, J. Cross-presentation by intercellular peptide transfer through gap junctions. Nature 434: 84–88, 2005.

    Article  Google Scholar 

  15. Valiunas, V., Polosina, Y., Miller, H., Potapova, I., Valiuniene, L., Doronin, S., Mathias, R.T., Robinson, R.B., Rosen, M.R., Cohen, I.S. and Brink, P.R. Connexin-specific cell-to-cell transfer of short interfering RNA by gap junctions. J. Physiol. 568: 459–468, 2005.

    Article  PubMed  CAS  Google Scholar 

  16. Wolvetang, E.J., M.F. Pera and K.S. Zuckerman, Gap junction mediated transport of shRNA between human embryonic stem cells. Biochem. Biophys. Res. Commun. 363(3): 610–615, 2007

    Article  PubMed  CAS  Google Scholar 

  17. Severs, N.J., E. Dupont, N. Thomas, R. Kaba, S. Rothery, R. Jain, K. Sharpey and C.H. Fry. Alterations in cardiac connexin expression in cardiomyopathies. Adv. Cardiol. 42: 228–242, 2006.

    Article  PubMed  CAS  Google Scholar 

  18. Bukauskas, F.F., M.M. Kreuzberg, M. Rackauskas, A. Bukauskiene, M.V.L. Bennett, V.K. Verselis and K. Willecke. Properties of mouse connexin 30.2 and human connexin 31.9 hemichannels: implications for atrioventricular conduction in the heart. Proc. Natl. Acad. Sci. USA. 103(25): 9726–9731, 2006.

    Article  PubMed  CAS  Google Scholar 

  19. Munshi, N., J. McAnally, S. Bezprozvannaya, J. Berry, J. Richardson, J. Hill, E. Olson Cx30.2 enhancer analysis identifies Gata4 as a novel regulator of atrioventricular delay. Development 136: 2665–2674, 2009

    Article  PubMed  CAS  Google Scholar 

  20. Belluardo, N., T.W. White, M. Srinivas, A. Trovato-Salinaro, H. Ripps, G. Mudo, R. Bruzzone and D.F. Condorelli. Identification and functional expression of HCx31.9. Cell Commun. Adhes. 8(4–6): 173–178, 2001.

    Article  PubMed  CAS  Google Scholar 

  21. White, T.W., M. Srinivas, H. Ripps, A. Trovato-Salinaro, D.F. Condorelli and R. Bruzzone. Virtual cloning, functional expression, and gating analysis of human connexin31.9. Am. J. Physiol. Cell Physiol. 283(3): C960–C967, 2002.

    PubMed  CAS  Google Scholar 

  22. Gemel, J., X. Lin, R. Collins, R.D. Veenstra, E.C. Beyer. Cx30.2 can form heteromeric gap junction channels with other cardiac connexins. (Abstract). Biochem Biophys Res Commun. 369: 388–394, 2008.

    Article  PubMed  CAS  Google Scholar 

  23. Yum, S., J. Zhang, V. Valiunas, G. Kanaporis, P.R. Brink, T. White, S. Scherer. Human connexins 26 and connexin 30 form functional heteromeric and heterotypic channels. Am. J. Physiol. 293: 1032–1048, 2007

    Article  Google Scholar 

  24. Valiunas, R., Doronin, S., Valiuniene, L., Potapova, I., Zuckerman, J., Walcott, B., Robinson, R.B., Rosen, M.R., Brink, P.R. and Cohen, I.S. Human mesenchymal stem cells make cardiac connexins and form functional gap junctions. J. Physiol. 555: 617–626, 2004.

    Article  PubMed  CAS  Google Scholar 

  25. Valiunas, V., R. Mui, E. McLachan, G. Valdimarsson, P.R. Brink, T. White Biophysical characterization of zebrafish connexin 35 hemichannels. Am. J. Physiol. 287:C1596–C1604, 2004.

    Article  CAS  Google Scholar 

  26. Mauritz, C., K. Schwanke, M. Reppel, S. Neff, K. Katsirntaki, L. Maier, F. Nguemo, S. Menke, M. Haustein, J. Hescheler, G. Hasenfuss, U. Martin Generation of functional murine cardiac myocytes from induced pluripotent stem cells. Circulation 118: 507–517, 2008

    Article  PubMed  Google Scholar 

  27. Worsdorfer, P., S. Maxeiner, C. Markopoulos, G. Kirfel, V. Wulf, T. Auth, S. Ureschel, J. von Maltzahn, K. Willecke Connexin expression and functional analysis of gap junctional communication in mouse embryonic stem cells 26: 431-439 2008

    Article  PubMed  Google Scholar 

  28. Huettner, J., A. Lu, Y. Qu, Y. Wu, M. Kim, J. McDonald Gap junctions and connexon hemichannels in human embryonic stem cells. Stem Cells 24: 1654–1667, 2006

    Article  PubMed  Google Scholar 

  29. Brink, P.R., K. Cronin, K. Banach, E. Peterson, E. Westphale, K.H. Seul, S.V. Ramanan and E.C. Beyer Evidence of heteromeric gap junction channels formed from rat connexin43 and human connexin37. Am. J. Physiol. 273: C1386–C1396, 1997.

    PubMed  CAS  Google Scholar 

  30. Valiunas, V., Gemel, J., Brink, P.R. and Beyer, E.C. Gap junction channels formed by Co-expressed Cx40 and Cx43. Am. J. Physiol. 281: H1675–H1688, 2001.

    CAS  Google Scholar 

  31. Barr, L., M. Dewey and Berger, W. Propagation of action potentials and the structure of the nexus in cardiac muscle. J. Gen. Physiol. 48: 797–823, 1965.

    Article  PubMed  CAS  Google Scholar 

  32. Weidmann, S. Electrical constants of trabecular muscle from mammalian heart. J. Physiol. 210: 1041–1054, 1970.

    PubMed  CAS  Google Scholar 

  33. Wilders, R., E.E. Verheijck, R. Kumar, W.N. Goolsby, A.C. van Ginneken, R.W. Joyner and H.J. Jongsma. Model clamp and its application to synchronization of rabbit sinoatrial node cells. Am. J. Physiol. 271: H2168–2182, 1996.

    PubMed  CAS  Google Scholar 

  34. Cole, W.C., J.B. Picone and N. Sperelakis. Gap junction uncoupling and discontinuous propagation in the heart. A comparison of experimental data with computer simulations. Biophys. J. 53(5): 809–818, 1988.

    Article  PubMed  CAS  Google Scholar 

  35. de Groot, J.R., T. Veenstra, A.O. Verkerk, R. Wilders, J.P. Smits, F.J. Wilms-Schopman, R.F Wiegerinck, J. Bourier, C.N. Belterman, R. Coronel and E.E. Verheijck. Conduction slowing by the gap junctional uncoupler carbenoxolone. Cardiovasc. Res. 60(2): 288–97, 2003.

    Article  PubMed  Google Scholar 

  36. Poelzing, S. and D.S. Rosenbaum. Altered connexin43 expression produces arrhythmia substrate in heart failure. Am. J. Physiol. Heart Circ. Physiol. 287: H1762–H1770, 2004.

    Article  PubMed  CAS  Google Scholar 

  37. Beauchamp, P., K. Yamada, A Baertschi, K. Green, E. Kanter, J. Saffitz, A. Kleber. Relative contributions of connexins 40 and 43 to atrial impulse propagation in synthetic strands of neonatal and fetal murine cardiomyocytes. Circ. Res. 99: 1216–1224, 2006

    Article  PubMed  CAS  Google Scholar 

  38. Janse, M. and A. Wit Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Phys. Rev. 69: 1049–1169, 1989.

    CAS  Google Scholar 

  39. Gutstein, D.E., G.E. Morley, D. Vaidya, F. Liu, F.L. Chen, H. Stuhlmann, G.I. Fishman Heterogeneous expression of Gap junction channels in the heart leads to conduction defects and ventricular dysfunction. Circulation 104: 1194–1199, 2001

    Article  PubMed  CAS  Google Scholar 

  40. Potapova, I., A. Plotnikov, Z. Lu, P. Danilo, Jr., W. Valiunas, J. Qu, S. Doronin, J. Zuckerman, I.N. Shlapakova, J. Gao, Z. Pan, A.J. Herron, R.B. Robinson, P.R. Brink, M.R. Rosen and I.S. Cohen Human mesenchymal stem cells as a gene delivery system to create cardiac pacemakers. Circ. Res. 94: 952–959, 2004.

    Article  PubMed  CAS  Google Scholar 

  41. Musil, L., B. Cunningham, G. Edelman, D. Goodenough Differential phosphorylation of the gap junction protein connexin 43 in junctional communication-competent and deficient cell lines J. Cell Biol. 111: 2077–2088, 1990

    Article  PubMed  CAS  Google Scholar 

  42. Pedrotty, D., R. Klinger, N. Badie, S. Hinds, A Kardashian, N. Bursac Structural coupling of cardiomyocytes and noncardiomyocytes: quantitative comparisons using a novel micropatterned cell pair assay. Am. J. Physiol. 295: H390–H400, 2008

    CAS  Google Scholar 

  43. Rosen A.B., D.J. Kelly, A.J. Schuldt, J. Lu, I.A. Potapova, S.V. Doronin, K.J. Robichaud, R.B. Robinson, M.R. Rosen, P.R. Brink, G.R. Gaudette, I.S. Cohen Finding fluorescent needles in the cardiac haystack: tracking human mesenchymal stem cells labeled with quantum dots for quantitative in vivo three-dimensional fluorescence analysis. Stem Cells 8: 2128–2138, 2007

    Article  Google Scholar 

  44. Severson, E., C. Parkos Mechanisms of outside-in signaling at the tight junction by junctional adhesion molecule A. Ann. N. Y. Acad. Sci. 1165: 10–18, 2009

    Article  PubMed  CAS  Google Scholar 

  45. Chen, Y., L. Xiang, J. Shao, R Pan, Y Wang, X Dong, R, Zhang Recruitment of endogenous bone marrow mesenchymal stem cells towards injured liver. J. Cell Mol. Med. 14: 1494–1508, 2010.

    Article  PubMed  Google Scholar 

  46. Potapova, I., P.R. Brink, I.S. Cohen, S.V. Doronin Culturing of human mesenchymal stem cells as 3D-aggregates induces functional expression of CXCR4 that regulates adhesion to endothelial cells. J. Biol. Chem. 283: 13100–13107, 2008

    Article  PubMed  CAS  Google Scholar 

  47. Camelliti, P., C. Green, I. LeGrice, P. Kohl Fibroblast network in rabbit sinoatrial node: structural and functional identification of homogenous and heterogenous cell coupling. Circ. Res. 94: 828–835, 2004

    Article  PubMed  CAS  Google Scholar 

  48. Graf, T., T. Enver Forcing cells to change lineage Nature 462: 587–594, 2009

    Article  PubMed  CAS  Google Scholar 

  49. Song, H., C. Yoon, S. Kattman, J. Dengler, S. Masse, T. Thavaratnam, M. Gewarges, K. Nanthakumar, M. Rubart, G. Keller, M. Radisic, P. Zandstra. Interrogating functional integration between injected pluripotent stem cell-derived cells and surrogate cardiac tissue. Proc. Natl. Acad. Sci. U S A 107: 3329–3334, 2010

    Article  PubMed  CAS  Google Scholar 

  50. Gollob, M.H., D.L. Jones, A.D. Krahn, L. Danis, X. Gong, Q. Shao, X. Liu, J.P. Veinot, A. Tang, A. Stewart, F. Tesson, G. Klein, R. Yee, A. Skanes, G. Guiraudon, L. Ebihara and D. Bai. Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. N. Engl. J. Med. 354: 25, 2006

    Article  Google Scholar 

  51. Kelly, D.J., A.B. Rosen, A.J. Schuldt, P.V. Kochupura, S.V. Doronin, I.A. Potapova, E.U. Azeloglu, S.F. Badlyak, P.R. Brink, I.S. Cohen, G.R. Gaudette Increased myocyte content and mechanical function within a tissue-engineered myocardial patch following implantation. Tissue Eng. Part A 15: 2189–2201, 2009

    Article  PubMed  CAS  Google Scholar 

  52. Valiunas, V., G. Kanaporis, L. Valiuniene, C Gordon, H. Wang, L. Li, R.B. Robinson, M.R. Rosen, I.S. Cohen, P.R. Brink Coupling an HCN2 expressing cell to a myocyte creates a two cell pacing unit. J. Physiol. 587: 5211–5226, 2009

    Article  Google Scholar 

  53. Potapova, I.A., Doronin, S.V., Kelly, D.J., Rosen, A.B., Schuldt, A.J., Lu, Z., Kochupura, P.V., Robinson, R.B., Rosen, MR., Brink, P.R., Gaudette, G.R., Cohen, I.S. Enhanced recovery of mechanical function in the canine heart by seeding an extracellular matrix patch with mesenchymal stem cells committed to a cardiac lineage. Am J Physiol Heart Circ Physiol. 295: H2257–63, 2008

    Article  PubMed  CAS  Google Scholar 

  54. Valiunas, V. Biophysical properties of connexin-45 gap junction hemichannels studied in vertebrate cells. J Gen Physiol. 119: 147–64, 2002

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY, 11794, USA

    Peter R. Brink

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  2. Ira S. Cohen
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  3. Richard T. Mathias
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Correspondence to Peter R. Brink .

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Editors and Affiliations

  1. Health Sciences Center, Dept. Physiology & Biophysics, Stony Brook University, Stony Brook, 11794-8661, New York, USA

    Ira S. Cohen

  2. Worcester Polytechnic Institute, Institute Rd. 100, Worcester, 01609-2280, Massachusetts, USA

    Glenn R. Gaudette

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Brink, P.R., Cohen, I.S., Mathias, R.T. (2011). Integration of Stem Cells into the Cardiac Syncytium: Formation of Gap Junctions. In: Cohen, I., Gaudette, G. (eds) Regenerating the Heart. Stem Cell Biology and Regenerative Medicine. Humana Press. https://doi.org/10.1007/978-1-61779-021-8_17

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