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Directing embryonic stem cell differentiation into osteogenic chondrogenic lineagein vitro

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Abstract

Regeneration of skeletal tissues is among the most promising areas of biological repair, providing a broad spectrum of potential clinical applications. In view of the ageing population and the worldwide shortage of donor tissue, tissue engineering is expected to become a major contributor to modern medicine. Recently, embryonic stem cells (ESCs) have received extensive attention due to their distinct biological properties, namely their unlimited self-renewal capacity and their pluripotency, which have rendered them a potent cell source for various medical and tissue engineering applications. The application of embryonic stem cells to skeletal tissue engineering requires inducing thein vitro differentiation of ESCs into the osteogenic and chondrogenic lineages. Although considerable progress has been made in directing embryonic stem cell differentiation towards the osteogenic and chondrogenic lineages, there are still obstacles remaining that need to be resolved before ESCs can be used as a suitable cell source in cell and tissue therapies. In particular, the efficient differentiation of ESCsin vitro towards the desired lineage requires the development of well-defined and proficient protocols, which would reduce the likelihood of spontaneous differentiation into divergent lineages and increase the available cell source for application to bone and cartilage tissue engineering therapies. Herein, this review provides a critical examination of the various experimental strategies that could be used to direct the differentiation of ESCs towards the skeletal tissuein vitro, especially the osteogenic and chondrogenic lineasges.

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References

  1. Keller, G. M. (1995)In vitro differentiation of embryonic stem cells.Curr. Opin. Cell Biol. 7: 862–869.

    Article  CAS  Google Scholar 

  2. Smith, A. G. (1991) Culture and differentiation of embryonic stem cells.Method Cell Sci. 13: 89–94.

    Google Scholar 

  3. Schuldiner, M., O. Yanuka, J. Itskovitz-Eldor, D. A. Melton, and N. Benvenisty (2000) Effects of eight growth factors on the differentiation of cells derived from human embryonic stem cells.Proc. Natl. Acad. Sci. USA 97: 11307–11312.

    Article  CAS  Google Scholar 

  4. Lu, C. C., J. Brennan, and E. J. Robertson (2001) From fertilization to gastrulation: Axis formation in the mouse embryo.Curr. Opin. Genet. Dev. 11: 384–392.

    Article  CAS  Google Scholar 

  5. Miura, T., M. P. Mattson, and M. S. Rao (2004) Cellular lifespan and senescence signaling in embryonic stem cells.Aging Cell 3: 333–343.

    Article  CAS  Google Scholar 

  6. Mauro, L. J. and D. N. Foster (2002) Regulators of telomerase activity.Am. J. Respir. Cell Mol. Biol. 26: 521–524.

    CAS  Google Scholar 

  7. Buckwalter, J. A. and H. J. Mankin (1998) Articular cartilage repair and transplantation.Arthritis Rheum. 41: 1331–1342.

    Article  CAS  Google Scholar 

  8. Zorn, A. M., K. Butler, and J. B. Gurdon (1999) Anterior endomesoderm specification in Xenopus by Wnt/beta-catenin and TGF-beta signalling pathways.Dev. Biol. 209: 282–297.

    Article  CAS  Google Scholar 

  9. Ladd, A. N., T. A. Yatskievych, and P. B. Antin (1998) Regulation of avian cardiac myogenesis by activin/ TGFbeta and bone morphogenetic proteins.Dev. Biol. 204: 407–419.

    Article  CAS  Google Scholar 

  10. Conley, B. J., J. C. Young, A. O. Trounson, and R. Mollard (2004) Derivation, propagation and differentiation of human embryonic stem cells.Int. J. Biochem. Cell Biol. 36: 555–567.

    Article  CAS  Google Scholar 

  11. Tam, P. P., E. A. Williams, and W. Y. Chan (1993) Gastrulation in the mouse embryo: Ultrastructural and molecular aspects of germ layer morphogenesis.Microsc. Res. Tech. 26: 301–328.

    Article  CAS  Google Scholar 

  12. Lawson, A. and G. C. Schoenwolf (2003) Epiblast and primitive-streak origins of the endoderm in the gastrulating chick embryo.Development 130: 3491–3501.

    Article  CAS  Google Scholar 

  13. Niederlander, C., J. J. Walsh, V. Episkopou, and C. M. Jones (2001) Arkadia enhances nodal-related signalling to induce mesendoderm.Nature 410: 830–834.

    Article  CAS  Google Scholar 

  14. Pfendler, K. C., C. S. Catuar, J. J. Meneses, and R. A. Pedersen (2005) Overexpression of Nodal promotes differentiation of mouse embryonic stem cells into mesoderm and endoderm at the expense of neuroectoderm formation.Stem Cells Dev. 14: 162–172.

    Article  CAS  Google Scholar 

  15. Grover, A. and E. D. Adamson (1985) Roles of extracellular matrix components in differentiating teratocarcinoma cells.J. Biol. Chem. 260: 12252–12258.

    CAS  Google Scholar 

  16. Herrmann, B. G. (1991) Expression pattern of the Brachyury gene in whole-mount TWis/TWis mutant embryos.Development 113: 913–917.

    CAS  Google Scholar 

  17. Kispert, A. and B. G. Herrman (1994) Immunohistochemical analysis of the Brachyury protein in wild-type and mutant mouse embryos.Dev. Biol. 161: 179–193.

    Article  Google Scholar 

  18. Colnot, C. (2005) Cellular and molecular interaction regulating skeletogenesis.J. Cell Biochem. 95: 688–697.

    Article  CAS  Google Scholar 

  19. Poliard, A., A. Nifuji, D. Lamblin, E. Plee, C. Forest, and O. Kellermann (1995) Controlled conversion of an immortalized mesodermal progenitor cell towards osteogenic, chondrogenic, or adipogenic pathways.J. Cell Biol. 130: 1461–1472.

    Article  CAS  Google Scholar 

  20. Erlebacher, A., E. H. Filvaroff, S. E. Gitelman, and R. Derynck (1995) Toward a molecular understanding of skeletal development.Cell 80: 371–378.

    Article  CAS  Google Scholar 

  21. Baker, J., J. P. Liu, E. J. Robertson, and A. Efstratiadis (1993) Role of insulin-like growth factors in embryonic and postnatal growth.Cell 75: 73–82.

    CAS  Google Scholar 

  22. Wozney, J. M. (1992) The bone morphogenetic protein family and osteogenesis.Mol. Reprod. Dev. 32. 160–167.

    Article  CAS  Google Scholar 

  23. Kingsley, D. M., A. E. Bland, J. M. Grubber, P. C. Marker, L. B. Russell, N. G. Copeland, and N. A. Jenkins (1992) The mouse short ear skeletal morphogenesis locus is associated with defects in a bone morphogenetic member of the TGFß superfamily.Cell 71: 399–410.

    Article  CAS  Google Scholar 

  24. Eames, B. F., P. T. Sharpe, and J. A. Helms (2004) Hierarchy revealed in the specification of three skeletal fates by Sox9 and Runx2.Dev. Biol. 274: 188–200.

    Article  CAS  Google Scholar 

  25. Itskovitz-Eldor, J., M. Schuldiner, D. Karsenti, A. Eden, O. Yanuka, M. Amit, H. Soreq, and N. Benvenisty (2000) Differentiation of human embryonic stem cells into embryoid bodies comprising the three embryonic germ layers.Mol. Med. 6: 88–95.

    CAS  Google Scholar 

  26. Tanaka, H., C. L. Murphy, C. Murphy, M. Kimura, S. Kawai, and J. M. Polak (2004) Chondrogenic differentiation of murine embryonic stem cells: Effects of culture conditions and dexamethasone.J. Cell. Biochem. 93: 454–462.

    Article  CAS  Google Scholar 

  27. Buttery, L. D., S. Bourne, J. D. Xynos, H. Wood, F. J. Hughes, S. P. Hughes, V. Episkopou, and J. M. Polak (2001) Differentiation of osteoblast andin vitro bone formation from murine embryonic stem cells.Tissue Eng. 7: 89–99.

    Article  CAS  Google Scholar 

  28. Mummery, C., D. Ward, C. E. van den Brink, S. D. Bird, P. A. Doevendans, T. Opthof, A. Brutel de la Riviere, L. Tertoolen, M. van der Heyden, and M. Pera (2002) Cardiomyocyte differentiation of mouse and human embryonic stem cells.J. Anat. 200: 233–242.

    Article  CAS  Google Scholar 

  29. Woll, N. L. and S. K. Bronson (2006) Analysis of embryonic stem cell-derived osteogenic cultures.Methods Mol. Biol. 330: 149–159.

    CAS  Google Scholar 

  30. Bielby, R. C., R. S. Pryce, L. L. Hench, and J. M. Polak (2005) Enhanced derivation of osteogenic cells from murine embryonic stem cells after treatment with ionic dissolution products of 58S bioactive sol-gel glass.Tissue Eng. 11: 479–488.

    Article  CAS  Google Scholar 

  31. Kawaguchi, J., P. J. Mee, and A. G. Smith (2005) Osteogenic and chondrogenic differentiation of embryonic stem cells in response to specific growth factors.Bone 36: 758–769.

    Article  CAS  Google Scholar 

  32. Kramer, J., C. Hegert, K. Guan, A. M. Wobus, P. K. Muller, and J. Rohwedel (2000) Embryonic stem cell-derived chondrogenic differentiationin vitro: Activation by BMP-2 and BMP-4.Mech. Dev. 92: 193–205.

    Article  CAS  Google Scholar 

  33. Kramer, J., M. Klinger, C. Kruse, M. Faza, G. Hargus, and J. Rohwedel (2005) Ultrastructural analysis of mouse embryonic stem cell-derived chondrocytes.Anat. Embryol. 210: 175–185.

    Article  Google Scholar 

  34. Nakayama, N., D. Duryea, R. Manoukian, G. Chow and C. Y. Han (2003) Macroscopic cartilage formation with embryonic stem-cell-derived mesodermal progenitor cells.J. Cell Sci. 116: 2015–2028.

    Article  CAS  Google Scholar 

  35. Hwang, Y. S., W. L. Randle, R. C. Bielby, J. M. Polak, and A. Mantalaris (2006) Enhanced derivation of osteogenic cells from murine embryonic stem cells after treatment with HepG2-conditioned medium and modulation of the embryoid body formation period: application to skeletal tissue engineering.Tissue Eng. 12: 1381–1392.

    Article  CAS  Google Scholar 

  36. Calhoun, J. D., R. R. Rao, S. Warrenfeltz, R. Rekaya, S. Dalton, J. McDonald, and S. L. Stice (2004) Transcriptional profiling of initial differentiation events in human embryonic stem cells.Biochem. Biophys. Res. Commun. 323: 453–464.

    Article  CAS  Google Scholar 

  37. Lake, J., J. Rathjen, J. Remiszewski, and P. D. Rathjen (2000) Reversible programming of pluripotent cell differentiation.J. Cell Sci. 113: 555–566.

    CAS  Google Scholar 

  38. Rathjen, J., J. A. Lake, M. D. Bettess, J. M. Washington, G. Chapman, and P. D. Rathjen (1999) Formation of a primitive ectoderm like cell population, EPL cells, from ES cells in response to biologically derived factors.J. Cell Sci. 112: 601–612.

    CAS  Google Scholar 

  39. Rudy-Reil, D. and J. Lough (2004) Avian precardiac endoderm/mesoderm induces cardiac myocyte differenttiation in murine embryonic stem cells.Circ. Res. 94: 107–116.

    Article  Google Scholar 

  40. Karp, J. M., L. S. Ferreira, A. Khademhosseini, A. H. Kwon, J. Yeh, and R. S. Langer (2006) Cultivation of human embryonic stem cells without the embryoid body step enhances osteogenesisin vitro.Stem Cells 24: 835–843.

    Article  Google Scholar 

  41. Lim, J. W. E. and A. Bodnar (2002) Proteome analysis of conditioned medium from mouse embryonic fibroblast feeder layer which support the growth of human embryonic stem cells.Proteomics 2: 1187–1203.

    Article  CAS  Google Scholar 

  42. Prowse, A. B. J., L. R. McQuade, K. J. Bryant, D. D. Van Dyk, B. E. Tuch, and P. P. Gray (2005) A proteome analysis of conditioned media from human neonatal fibroblasts used in the maintenance of human embryonic stem cells.Proteomics 5: 978–989.

    Article  CAS  Google Scholar 

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  1. Department of Chemical Engineering, Imperial College London, South Kensington Campus, SW7 2AZ, London, UK

    Yu-Shik Hwang, Yunyi Kang & Athanasios Mantalaris

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  1. Yu-Shik Hwang
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  2. Yunyi Kang
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Correspondence to Athanasios Mantalaris.

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Hwang, YS., Kang, Y. & Mantalaris, A. Directing embryonic stem cell differentiation into osteogenic chondrogenic lineagein vitro . Biotechnol. Bioprocess Eng. 12, 15–21 (2007). https://doi.org/10.1007/BF02931798

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