Pediatric Cardiology

, Volume 30, Issue 5, pp 635–642 | Cite as

Natural and Synthetic Regulators of Embryonic Stem Cell Cardiogenesis

Riley Symposium

Abstract

Debilitating cardiomyocyte loss underlies the progression to heart failure. Although there have been significant advances in treatment, current therapies are intended to improve or preserve heart function rather than regenerate lost myocardium. A major hurdle in implementing a cell-based regenerative therapy is the inefficient differentiation of cardiomyocytes from either endogenous or exogenous stem cell sources. Moreover, cardiomyocytes that develop in human embryonic stem cell (hESC) or human-induced pluripotent stem cell (hIPSC) cultures are comparatively immature, even after prolonged culture, and differences in their calcium handling, ion channel, and force generation properties relative to adult cardiomyocytes raise concerns of improper integration and function after transplantation. Thus, the discovery of natural and novel small molecule synthetic regulators of differentiation and maturation would accelerate the development of stem-cell-based myocardial therapies. Here, we document recent advances in defining natural signaling pathways that direct the multistep cardiomyogenic differentiation program and the development of small molecules that might be used to enhance differentiation as well as the potential characteristics of lead candidates for pharmaceutical stimulation of endogenous myocardial replacement.

Keywords

Cardiomyocyte Embryonic stem cell Chemical screening 

References

  1. 1.
    Binah O, Dolnikov K, Sadan O, Shilkrut M, Zeevi-Levin N, Amit M, Danon A, Itskovitz-Eldor J (2007) Functional and developmental properties of human embryonic stem cells-derived cardiomyocytes. J Electrocardiol 40:S192–S196PubMedCrossRefGoogle Scholar
  2. 2.
    Boshoff HI, Dowd CS (2007) Chemical genetics: an evolving toolbox for target identification and lead optimization. Prog Drug Res 64(49):51–77CrossRefGoogle Scholar
  3. 3.
    Bushway PJ, Mercola M (2006) High-throughput screening for modulators of stem cell differentiation. Methods Enzymol 414:300–316PubMedCrossRefGoogle Scholar
  4. 4.
    Bushway PJ, Mercola M, Price JH (2008) A comparative analysis of standard microtiter plate reading versus imaging in cellular assays. Assay Drug Dev Technol 6:557–567PubMedCrossRefGoogle Scholar
  5. 5.
    Campa VM, Gutierrez-Lanza R, Cerignoli F, Diaz-Trelles R, Nelson B, Tsuji T, Barcova M, Jiang W, Mercola M (2008) Notch activates cell cycle reentry and progression in quiescent cardiomyocytes. J Cell Biol 183:129–141PubMedCrossRefGoogle Scholar
  6. 6.
    Chen VC, Stull R, Joo D, Cheng X, Keller G (2008) Notch signaling respecifies the hemangioblast to a cardiac fate. Nat Biotechnol 26:1169–1178PubMedCrossRefGoogle Scholar
  7. 7.
    Collesi C, Zentilin L, Sinagra G, Giacca M (2008) Notch1 signaling stimulates proliferation of immature cardiomyocytes. J Cell Biol 183:117–128PubMedCrossRefGoogle Scholar
  8. 8.
    D’Amour KA, Agulnick AD, Eliazer S, Kelly OG, Kroon E, Baetge EE (2005) Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat Biotechnol 23:1534–1541PubMedCrossRefGoogle Scholar
  9. 9.
    Darvas F, Dorman G, Krajcsi P, Puskas LG, Kovari Z, Lorincz Z, Urge L (2004) Recent advances in chemical genomics. Curr Med Chem 11:3119–3145PubMedGoogle Scholar
  10. 10.
    De Tullio MC, Arrigoni O (2004) (2004) Hopes, disillusions and more hopes from vitamin C. Cell Mol Life Sci 61:209–219PubMedCrossRefGoogle Scholar
  11. 11.
    Dinsmore J, Ratliff J, Deacon T, Pakzaban P, Jacoby D, Galpern W, Isacson O (1996) Embryonic stem cells differentiated in vitro as a novel source of cells for transplantation. Cell Transplant 5:131–143PubMedCrossRefGoogle Scholar
  12. 12.
    Dolnikov K, Shilkrut M, Zeevi-Levin N, Gerecht-Nir S, Amit M, Danon A, Itskovitz-Eldor J, Binah O (2006) Functional properties of human embryonic stem cell-derived cardiomyocytes: intracellular Ca2+ handling and the role of sarcoplasmic reticulum in the contraction. Stem Cells 24:236–245PubMedCrossRefGoogle Scholar
  13. 13.
    Foley AC, Mercola M (2005) Heart induction by Wnt antagonists depends on the homeodomain transcription factor Hex. Genes Dev 19:387–396PubMedCrossRefGoogle Scholar
  14. 14.
    Foley AC, Korol O, Timmer AM, Mercola M (2007) Multiple functions of Cerberus cooperate to induce heart downstream of Nodal. Dev Biol 303:57–65PubMedCrossRefGoogle Scholar
  15. 15.
    Fransioli J, Bailey B, Gude NA, Cottage CT, Muraski JA, Emmanuel G, Wu W, Alvarez R, Rubio M, Ottolenghi S, Schaefer E, Sussman MA (2008) Evolution of the c-kit-positive cell response to pathological challenge in the myocardium. Stem Cells 26:1315–1324PubMedCrossRefGoogle Scholar
  16. 16.
    Gadue P, Huber TL, Paddison PJ, Keller GM (2006) Wnt and TGF-beta signaling are required for the induction of an in vitro model of primitive streak formation using embryonic stem cells. Proc Natl Acad Sci USA 103:16806–16811Google Scholar
  17. 17.
    Hsieh PC, Segers VF, Davis ME, MacGillivray C, Gannon J, Molkentin JD, Robbins J, Lee RT (2007) Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nat Med 13:970–974PubMedCrossRefGoogle Scholar
  18. 18.
    Inman GJ, Nicolas FJ, Callahan JF, Harling JD, Gaster LM, Reith AD, Laping NJ, Hill CS (2002) SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol Pharmacol 62:65–74PubMedCrossRefGoogle Scholar
  19. 19.
    Kan N, Talantova M, Chen HSV, Mercola M (2008) Selection of cardiomyocytes from differentiating human induced pluripotent stem cells (in review)Google Scholar
  20. 20.
    Kehat I, Gepstein A, Spira A, Itskovitz-Eldor J, Gepstein L (2002) High-resolution electrophysiological assessment of human embryonic stem cell-derived cardiomyocytes: a novel in vitro model for the study of conduction. Circ Res 91:659–661PubMedCrossRefGoogle Scholar
  21. 21.
    Kita-Matsuo H, Barcova M, Prighozhina N, Salomonis N, Wei K, Jacot JG, Nelson B, Spiering S, Haverslag R, Kim C, Talantova M, Terskikh A, McCulloch AD, Price JH, Conklin BR, Chen HSV, Mercola M (2009) Lentiviral vectors and protocols for creation of stable hESC lines for fluorescent tracking and drug resistance selection of cardiomyocytes. PLoS ONE (in press)Google Scholar
  22. 22.
    Korol O, Gupta RW, Mercola M (2008) A novel activity of the Dickkopf-1 amino terminal domain promotes axial and heart development independently of canonical Wnt inhibition. Dev Biol 324:131–138PubMedCrossRefGoogle Scholar
  23. 23.
    Kubo H, Jaleel N, Kumarapeli A, Berretta RM, Bratinov G, Shan X, Wang H, Houser SR, Margulies KB (2008) Increased cardiac myocyte progenitors in failing human hearts. Circulation 118:649–657PubMedCrossRefGoogle Scholar
  24. 24.
    Kwon C, Arnold J, Hsiao EC, Taketo MM, Conklin BR, Srivastava D (2007) Canonical Wnt signaling is a positive regulator of mammalian cardiac progenitors. Proc Natl Acad Sci USA 104:10894–10899Google Scholar
  25. 25.
    Laflamme MA, Gold J, Xu C, Hassanipour M, Rosler E, Police S, Muskheli V, Murry CE (2005) Formation of human myocardium in the rat heart from human embryonic stem cells. Am J Pathol 167:663–671PubMedGoogle Scholar
  26. 26.
    Laflamme MA, Chen KY, Naumova AV, Muskheli V, Fugate JA, Dupras SK, Reinecke H, Xu C, Hassanipour M, Police S, O’Sullivan C, Collins L, Chen Y, Minami E, Gill EA, Ueno S, Yuan C, Gold J, Murry CE (2007) Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol 25:1015–1024PubMedCrossRefGoogle Scholar
  27. 27.
    Lindsley RC, Gill JG, Kyba M, Murphy TL, Murphy KM (2006) Canonical Wnt signaling is required for development of embryonic stem cell-derived mesoderm. Development 133:3787–3796PubMedCrossRefGoogle Scholar
  28. 28.
    Liu J, Fu JD, Siu CW, Li RA (2007) Functional sarcoplasmic reticulum for calcium handling of human embryonic stem cell-derived cardiomyocytes: insights for driven maturation. Stem Cells 25:3038–3044PubMedCrossRefGoogle Scholar
  29. 29.
    Marvin MJ, Di Rocco G, Gardiner A, Bush SM, Lassar AB (2001) Inhibition of Wnt activity induces heart formation from posterior mesoderm. Genes Dev 15:316–327PubMedCrossRefGoogle Scholar
  30. 30.
    Naito AT, Shiojima I, Akazawa H, Hidaka K, Morisaki T, Kikuchi A, Komuro I (2006) Developmental stage-specific biphasic roles of Wnt/beta-catenin signaling in cardiomyogenesis and hematopoiesis. Proc Natl Acad Sci USA 103:19812–19817Google Scholar
  31. 31.
    Olson EN, Schneider MD (2003) Sizing up the heart: development redux in disease. Genes Dev 17:1937–1956PubMedCrossRefGoogle Scholar
  32. 32.
    Qyang Y, Martin-Puig S, Chiravuri M, Chen S, Xu H, Bu L, Jiang X, Lin L, Granger A, Moretti A, Caron L, Wu X, Clarke J, Taketo MM, Laugwitz KL, Moon RT, Gruber P, Evans SM, Ding S, Chien KR (2007) The renewal and differentiation of Isl1+ cardiovascular progenitors are controlled by a Wnt/beta-catenin pathway. Cell Stem Cell 1:165–179PubMedCrossRefGoogle Scholar
  33. 33.
    Sadek H, Hannack B, Choe E, Wang J, Latif S, Garry MG, Garry DJ, Longgood J, Frantz DE, Olson EN, Hsieh J, Schneider JW (2008) Cardiogenic small molecules that enhance myocardial repair by stem cells. Proc Natl Acad Sci USA 105:6063–6068PubMedCrossRefGoogle Scholar
  34. 34.
    Schneider VA, Mercola M (2001) Wnt antagonism initiates cardiogenesis in Xenopus laevis. Genes Dev 15:304–315PubMedCrossRefGoogle Scholar
  35. 35.
    Takahashi T, Lord B, Schulze PC, Fryer RM, Sarang SS, Gullans SR, Lee RT (2003) Ascorbic acid enhances differentiation of embryonic stem cells into cardiac myocytes. Circulation 107:1912–1916PubMedCrossRefGoogle Scholar
  36. 36.
    Ueno S, Weidinger G, Osugi T, Kohn AD, Golob JL, Pabon L, Reinecke H, Moon RT, Murry CE (2007) Biphasic role for Wnt/beta-catenin signaling in cardiac specification in zebrafish and embryonic stem cells. Proc Natl Acad Sci USA 104:9685–9690PubMedCrossRefGoogle Scholar
  37. 37.
    van Laake LW, Passier R, Doevendans PA, Mummery CL (2008) Human embryonic stem cell-derived cardiomyocytes and cardiac repair in rodents. Circ Res 102:1008–1010PubMedCrossRefGoogle Scholar
  38. 38.
    Wei ZL, Petukhov PA, Bizik F, Teixeira JC, Mercola M, Volpe EA, Glazer RI, Willson TM, Kozikowski AP (2004) Isoxazolyl-serine-based agonists of peroxisome proliferator-activated receptor: design, synthesis, and effects on cardiomyocyte differentiation. J Am Chem Soc 126:16714–16715Google Scholar
  39. 39.
    Willems E, Leyns L (2008) Patterning of mouse embryonic stem cell-derived pan-mesoderm by Activin A/Nodal and Bmp4 signaling requires fibroblast growth factor activity. Differentiation 76(7):745–759PubMedCrossRefGoogle Scholar
  40. 40.
    Wu X, Ding S, Ding Q, Gray NS, Schultz PG (2004) Small molecules that induce cardiomyogenesis in embryonic stem cells. J Am Chem Soc 126:1590–1591PubMedCrossRefGoogle Scholar
  41. 41.
    Xu C, Police S, Rao N, Carpenter MK (2002) Characterization and enrichment of cardiomyocytes derived from human embryonic stem cells. Circ Res 91:501–508PubMedCrossRefGoogle Scholar
  42. 42.
    Xu Y, Shi Y, Ding S (2008) A chemical approach to stem-cell biology and regenerative medicine. Nature 453:338–344PubMedCrossRefGoogle Scholar
  43. 43.
    Yang L, Soonpaa MH, Adler ED, Roepke TK, Kattman SJ, Kennedy M, Henckaerts E, Bonham K, Abbott GW, Linden RM, Field LJ, Keller GM (2008) Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population. Nature 453:524–528PubMedCrossRefGoogle Scholar
  44. 44.
    Yasunaga M, Tada S, Torikai-Nishikawa S, Nakano Y, Okada M, Jakt LM, Nishikawa S, Chiba T, Era T, Nishikawa S (2005) Induction and monitoring of definitive and visceral endoderm differentiation of mouse ES cells. Nat Biotechnol 23:1542–1550PubMedCrossRefGoogle Scholar
  45. 45.
    Zhang Q, Major MB, Takanashi S, Camp ND, Nishiya N, Peters EC, Ginsberg MH, Jian X, Randazzo PA, Schultz PG, Moon RT, Ding S (2007) Small-molecule synergist of the Wnt/beta-catenin signaling pathway. Proc Natl Acad Sci USA 104:7444–7448PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Burnham Institute for Medical ResearchLa JollaUSA

Personalised recommendations