European Spine Journal

, Volume 23, Supplement 3, pp 364–374

Cell sources for nucleus pulposus regeneration

  • Nevenka Kregar Velikonja
  • Jill Urban
  • Mirjam Fröhlich
  • Cornelia Neidlinger-Wilke
  • Dimitris Kletsas
  • Urska Potocar
  • Sarah Turner
  • Sally Roberts
Review article

Abstract

Purpose

There is increasing interest in the development of cell therapy as a possible approach for the treatment of degenerative disc disease. To regenerate nucleus pulposus tissue, the cells must produce an appropriate proteoglycan-rich matrix, as this is essential for the functioning of the intervertebral disc. The natural environment within the disc is very challenging to implanted cells, particularly if they have been subcultured in normal laboratory conditions. The purpose of this work is to discuss parameters relevant to translating different proposed cell therapies of IVD into clinical use.

Results

Several sources of cells have been proposed, including nucleus pulposus cells, chondrocytes and mesenchymal stem cells derived from bone marrow or adipose tissue. There are some clinical trials and reports of attempts to regenerate nucleus pulposus utilising either autologous or allogenic cells. While the published results of clinical applications of these cell therapies do not indicate any safety issues, additional evidence will be needed to prove their long-term efficacy.

Conclusion

This article discusses parameters relevant for successful translation of research on different cell sources into clinically applicable cell therapies: the influence of the intervertebral disc microenvironment on the cell phenotype, issues associated with cell culture and technical preparation of cell products, as well as discussing current regulatory requirements. There are advantages and disadvantages of each proposed cell type, but no strong evidence to favour any one particular cell source at the moment.

Keywords

Intervertebral disc regeneration Cell implantation Differentiation Microenvironmental factors Cell products Regulatory and governance issues 

References

  1. 1.
    Meisel HJ, Siodla V, Ganey T, Minkus Y, Hutton WC, Alasevic O (2007) Clinical experience in cell-based therapeutics: disc chondrocyte transplantation: a treatment for degenerated or damaged intervertebral disc. Biomol Eng 24:5–21PubMedGoogle Scholar
  2. 2.
    Sakai D, Mochida J, Iwashina T, Watanabe T, Nakai T, Ando K, Hotta T (2005) Differentiation of mesenchymal stem cells transplanted to a rabbit degenerative disc level. Spine 30:2379–2387PubMedGoogle Scholar
  3. 3.
    Okuma M, Mochida J, Nishimura K, Sakabe K, Seiki K (2000) Reinsertion of stimulated nucleus pulposus cells retards intervertebral disc degeneration: an in vitro and in vivo experimental study. J Orthop Res 18:988–997PubMedGoogle Scholar
  4. 4.
    Ganey T, Libera J, Moos V, Alasevic O, Fritsch K-G, Meisel HJ, Hutton WC (2003) Disc chondrocyte transplantation in a canine model: a treatment for degenerated or damaged intervertebral disc. Spine 28:2609–2620PubMedGoogle Scholar
  5. 5.
    Ho G, Leung VY, Cheung KM, Chan D (2008) Effect of severity of intervertebral disc injury on mesenchymal stem cell-based regeneration. Connect Tissue Res 49:15–21PubMedGoogle Scholar
  6. 6.
    Zhang YG, Guo X, Xu P, Kang LL, Li J (2005) Bone mesenchymal stem cells transplanted into rabbit intervertebral discs can increase proteoglycans. Clin Orthop Relat Res 430:219–226Google Scholar
  7. 7.
    Gorensek M, Jaksimoviæ C, Kregar-Velikonja N, Gorensek M, Knezevic M, Jeras M, Pavlovcic V, Cör A (2004) Nucleus pulposus repair with cultured autologous elastic cartilage derived chondrocytes. Cell Mol Biol Lett 9:363–374PubMedGoogle Scholar
  8. 8.
    Alphatec Spine Inc. Radiographic and Clinical Outcomes of PureGen in Posterior Lumbar (PLIF) and Transforaminal Interbody Fusion (TLIF). Clinicaltrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01293981?term=nct01293981&rank=1.9-3-201220-12-2012
  9. 9.
    NuVasive. Osteocel® Plus in eXtreme Lateral Interbody Fusion (XLIF®). Clinicaltrials.gov http://www.clinicaltrials.gov/ct2/show/NCT00948532?term=nct00948532&rank=1.10-6-201120-12-0012
  10. 10.
    Kandel R, Roberts S, Urban JPG (2008) Tissue engineering of the intervertebral disc. Eur Spine J 17(Suppl 4):480–491PubMedCentralPubMedGoogle Scholar
  11. 11.
    Grunhagen T, Shirazi-Adl A, Fairbank JC, Urban JP (2011) Intervertebral disk nutrition: a review of factors influencing concentrations of nutrients and metabolites. Orthop Clin North Am 42:465–477PubMedGoogle Scholar
  12. 12.
    Wuertz K, Godburn K, Neidlinger-Wilke C, Urban J, Iatridis JC (2008) Behavior of mesenchymal stem cells in the chemical microenvironment of the intervertebral disc. Spine (Phila Pa 1976) 33:1843–1849Google Scholar
  13. 13.
    Roughley PJ (2004) Biology of intervertebral disc aging and degeneration. Spine 29:2691–2699PubMedGoogle Scholar
  14. 14.
    Peacock A (1951) Observations on the pre-natal development of the intervertebral disc in man. J Anat 85:260–274PubMedCentralPubMedGoogle Scholar
  15. 15.
    Walmsley R (1953) The development and growth of the intervertebral disc. Edinb Med J 60(8):341–364PubMedGoogle Scholar
  16. 16.
    Hunter CJ, Matyas JR, Duncan NA (2004) Cytomorphology of notochordal and chondrocyte cells from the nucleus pulposus: a species comparison. J Anat 205:357–362PubMedCentralPubMedGoogle Scholar
  17. 17.
    Trout JJ, Buckwalter JA, Moore KC, Landas SK (1982) Ultrastructure of the human intervertebral disc. I. Changes in notochordal cells with age. Tissue Cell 14:359–369PubMedGoogle Scholar
  18. 18.
    Roberts S, Evans H, Trivedi J, Menage J (2006) Histology and pathology of the human intervertebral disc. J Bone Jt Surg 88-A:10–14Google Scholar
  19. 19.
    Guehring T, Wilde G, Sumner M, Grünhagen T, Karney GB, Tirlapur UK, Urban JPG (2009) Notochordal intervertebral disc cells: sensitivity to nutrient deprivation. Arthr Rheum 60:1026–1034Google Scholar
  20. 20.
    Risbud MV, Shapiro IM (2011) Notochordal cells in the adult intervertebral disc: new perspective on an old question. Crit Rev Eukaryot Gene Expr 21:29–41PubMedCentralPubMedGoogle Scholar
  21. 21.
    Minogue BM, Richardson SM, Zeef LA, Freemont AJ, Hoyland JA (2010) Characterization of the human nucleus pulposus cell phenotype and evaluation of novel marker gene expression to define adult stem cell differentiation. Arthr Rheum 62:3695–3705Google Scholar
  22. 22.
    Sakai D, Nakai T, Mochida J, Alini M, Grad S (2009) Differential phenotype of intervertebral disc cells: microarray and immunohistochemical analysis of canine nucleus pulposus and anulus fibrosus. Spine (Phila Pa 1976) 34:1448–1456Google Scholar
  23. 23.
    Gilson A, Dreger M, Urban JP (2010) Differential expression level of cytokeratin 8 in cells of the bovine nucleus pulposus complicates the search for specific intervertebral disc cell markers. Arthr Res Ther 12:R24Google Scholar
  24. 24.
    Weiler C, Nerlich AG, Schaaf R, Bachmeier BE, Wuertz K, Boos N (2010) Immunohistochemical identification of notochordal markers in cells in the aging human lumbar intervertebral disc. Eur Spine J 19:1761–1770PubMedCentralPubMedGoogle Scholar
  25. 25.
    Carragee EJ, Don AS, Hurwitz EL, Cuellar JM, Carrino JA, Herzog R (2009) 2009 ISSLS prize winner: does discography cause accelerated progression of degeneration changes in the lumbar disc: a ten-year matched cohort study. Spine (Phila Pa 1976) 34:2338–2345Google Scholar
  26. 26.
    Drazin D, Rosner J, Avalos P, Acosta F (2012) Stem cell therapy for degenerative disc disease. Adv Orthop 2012:961052PubMedCentralPubMedGoogle Scholar
  27. 27.
    Henriksson H, Hagman M, Horn M, Lindahl A, Brisby H (2011) Investigation of different cell types and gel carriers for cell-based intervertebral disc therapy, in vitro and in vivo studies. J Tissue Eng Regen Med. doi:10.1002/term.480
  28. 28.
    Richardson SM, Hoyland JA, Mobasheri R, Csaki C, Shakibaei M, Mobasheri A (2010) Mesenchymal stem cells in regenerative medicine: opportunities and challenges for articular cartilage and intervertebral disc tissue engineering. J Cell Physiol 222:23–32PubMedGoogle Scholar
  29. 29.
    Sakai D (2011) Stem cell regeneration of the intervertebral disk. Orthop Clin North Am 42:555–562PubMedGoogle Scholar
  30. 30.
    Lee CR, Sakai D, Nakai T, Toyama K, Mochida J, Alini M, Grad S (2007) A phenotypic comparison of intervertebral disc and articular cartilage cells in the rat. Eur Spine J 16:2174–2182PubMedCentralPubMedGoogle Scholar
  31. 31.
    Rutges J, Creemers LB, Dhert W, Milz S, Sakai D, Mochida J, Alini M, Grad S (2010) Variations in gene and protein expression in human nucleus pulposus in comparison with annulus fibrosus and cartilage cells: potential associations with aging and degeneration. Osteoarthr Cartil 18:416–423PubMedGoogle Scholar
  32. 32.
    Power KA, Grad S, Rutges JP, Creemers LB, van Rijen MH, O’Gaora P, Wall JG, Alini M, Pandit A, Gallagher WM (2011) Identification of cell surface-specific markers to target human nucleus pulposus cells: expression of carbonic anhydrase XII varies with age and degeneration. Arthr Rheum 63:3876–3886Google Scholar
  33. 33.
    Minogue BM, Richardson SM, Zeef LA, Freemont AJ, Hoyland JA (2010) Transcriptional profiling of bovine intervertebral disc cells: implications for identification of normal and degenerate human intervertebral disc cell phenotypes. Arthr Res Ther 12:R22Google Scholar
  34. 34.
    Sobajima S, Vadala G, Shimer A, Kim JS, Gilbertson L, Kang JD (2008) Feasibility of a stem cell therapy for intervertebral disc degeneration. Spine J 4:S117–S125Google Scholar
  35. 35.
    Sheikh H, Zakharian K, De La Torre RP, Facek C, Vasquez A, Chaudhry GR, Svinarich D, Perez-Cruet MJ (2009) In vivo intervertebral disc regeneration using stem cell-derived chondroprogenitors. J Neurosurg Spine 10:265–272PubMedGoogle Scholar
  36. 36.
    Brisby H, Papadimitriou N, Brantsing C, Bergh P, Lindahl A, Barreto HH (2012) The presence of local mesenchymal progenitor cells in human degenerated intervertebral discs and possibilities to influence these in vitro: a descriptive study in humans. Stem Cells Dev 22(5):804–814PubMedGoogle Scholar
  37. 37.
    Risbud MV, Guttapalli A, Tsai TT, Lee JY, Danielson KG, Vaccaro AR, Albert TJ, Gazit Z, Gazit D, Shapiro IM (2007) Evidence for skeletal progenitor cells in the degenerate human intervertebral disc. Spine (Phila Pa 1976) 32:2537–2544Google Scholar
  38. 38.
    Blanco JF, Graciani IF, Sanchez-Guijo FM, Muntion S, Hernandez-Campo P, Santamaria C, Carrancio S, Barbado MV, Cruz G, Gutierrez-Cosio S, Herrero C, San Miguel JF, Brinon JG, del Canizo MC (2010) Isolation and characterization of mesenchymal stromal cells from human degenerated nucleus pulposus: comparison with bone marrow mesenchymal stromal cells from the same subjects. Spine (Phila Pa 1976) 35:2259–2265Google Scholar
  39. 39.
    Huang B, Liu LT, Li CQ, Zhuang Y, Luo G, Hu SY, Zhou Y (2012) Study to determine the presence of progenitor cells in the degenerated human cartilage endplates. Eur Spine J 21:613–622PubMedCentralPubMedGoogle Scholar
  40. 40.
    Hee HT, Ismail HD, Lim CT, Goh JC, Wong HK (2010) Effects of implantation of bone marrow mesenchymal stem cells, disc distraction and combined therapy on reversing degeneration of the intervertebral disc. J Bone Joint Surg Br 92:726–736PubMedGoogle Scholar
  41. 41.
    Goldschlager T, Ghosh P, Zannettino A, Gronthos S, Rosenfeld JV, Itescu S, Jenkin G (2010) Cervical motion preservation using mesenchymal progenitor cells and pentosan polysulfate, a novel chondrogenic agent: preliminary study in an ovine model. Neurosurg Focus 28:E4PubMedGoogle Scholar
  42. 42.
    Vadala G, Sowa G, Hubert M, Gilbertson LG, Denaro V, Kang JD (2012) Mesenchymal stem cells injection in degenerated intervertebral disc: cell leakage may induce osteophyte formation. J Tissue Eng Regen Med 6:348–355PubMedGoogle Scholar
  43. 43.
    Acosta FL, Metz L, Adkisson HD, Liu J, Carruthers-Liebenberg E, Milliman C, Maloney M, Lotz JC (2011) Porcine intervertebral disc repair using allogeneic juvenile articular chondrocytes or mesenchymal stem cells. Tissue Eng Part A 17:3045–3055PubMedCentralPubMedGoogle Scholar
  44. 44.
    Kluba T, Niemeyer T, Gaissmaier C, Gründer T (2005) Human anulus fibrosis and nucleus pulposus cells of the intervertebral disc. Effect of degeneration and culture system on cell phenotype. Spine 30:2743–2748PubMedGoogle Scholar
  45. 45.
    Roberts S, Evans EH, Kletsas D, Jaffray DC, Eisenstein SM (2006) Senescence in human intervertebral discs. Eur Spine J 15:S312–S316PubMedGoogle Scholar
  46. 46.
    Park J-B, Chang H, Kim K-W (2001) Expression of Fas ligand and apoptosis of disc cells in herniated lumbar disc tissue. Spine 26:618–621PubMedGoogle Scholar
  47. 47.
    Brock M, Patt S, Mayer HM (1992) The form and structure of the extruded disc. Spine 17:1457–1461PubMedGoogle Scholar
  48. 48.
    Yasuma T, Arai K, Yamauchi Y (2001) The histology of lumbar intervertebral disc herniation: the significance of small blood vessels in the extruded tissue. Spine 18:1761–1765Google Scholar
  49. 49.
    Schmid G, Witteler A, Willburger R, Kuhnen C, Jergas M, Koester O (2004) Lumbar disc herniation: correlation of histologic findings with marrow signal intensity changes in vertebral endplates at MR Imaging. Radiology 231:352–358PubMedGoogle Scholar
  50. 50.
    Erwin WM, Inman RD (2006) Notochord cells regulate intervertebral disc chondrocyte proteoglycan production and cell proliferation. Spine (Phila Pa 1976) 31:1094–1099Google Scholar
  51. 51.
    Purmessur D, Schek RM, Abbott RD, Ballif BA, Godburn KE, Iatridis JC (2011) Notochordal conditioned media from tissue increases proteoglycan accumulation and promotes a healthy nucleus pulposus phenotype in human mesenchymal stem cells. Arthr Res Ther 13:R81Google Scholar
  52. 52.
    Takahashi I, Nuckolls GH, Takahashi K, Tanaka O, Semba I, Dashner R, Shum L, Slavkin HC (1998) Compressive force promotes sox9, type II collagen and aggrecan and inhibits IL-1 beta expression resulting in chondrogenesis in mouse embryonic limb bud mesenchymal cells. J Cell Sci 111(Pt 14):2067–2076PubMedGoogle Scholar
  53. 53.
    Cui Y, Yu J, Urban JPG, Young DA (2010) Differential gene expression profiling of metalloproteinases and their inhibitors: a comparison between bovine intervertebral disc nucleus pulposus cells and articular chondrocytes. Spine 35:1101–1108PubMedGoogle Scholar
  54. 54.
    Mwale F, Roughley P, Antoniou J (2004) Distinction between the extracellular matrix of the nucleus pulposus and hyaline cartilage: a requisite for tissue engineering of intervertebral disc. Eur Cell Mater 8:58–64PubMedGoogle Scholar
  55. 55.
    Maroudas A, Stockwell RA, Nachemson A, Urban J (1975) Factors involved in the nutrition of the human lumbar intervertebral disc: cellularity and diffusion of glucose in vitro. J Anat 120:113–130PubMedCentralPubMedGoogle Scholar
  56. 56.
    Liebscher T, Haefeli M, Wuertz K, Nerlich AG, Boos N (2011) Age-related variation in cell density of human lumbar intervertebral disc. Spine (Phila Pa 1976) 36:153–159Google Scholar
  57. 57.
    Baer PC, Geiger H (2012) Adipose-derived mesenchymal stromal/stem cells: tissue localization, characterization, and heterogeneity. Stem Cells Int 2012:812693PubMedCentralPubMedGoogle Scholar
  58. 58.
    Li J, Wong WH, Chan S, San Chim JC, Cheung KM, Lee TL, Au WY, Ha SY, Lie AK, Lau YL, Liang RH, Chan GC (2011) Factors affecting mesenchymal stromal cells yield from bone marrow aspiration. Chin J Cancer Res 23:43–48PubMedCentralPubMedGoogle Scholar
  59. 59.
    Velikonja NK, Wozniak G, Malicev E, Knezevic M, Jeras M (2001) Protein synthesis of human articular chondrocytes cultured in vitro for autologous transplantation. Pflugers Arch 442:R169–R170PubMedGoogle Scholar
  60. 60.
    Lee J, Lee E, Kim HY, Son Y (2007) Comparison of articular cartilage with costal cartilage in initial cell yield, degree of dedifferentiation during expansion and redifferentiation capacity. Biotechnol Appl Biochem 48:149–158PubMedGoogle Scholar
  61. 61.
    Yang KG, Saris DB, Geuze RE, Helm YJ, Rijen MH, Verbout AJ, Dhert WJ, Creemers LB (2006) Impact of expansion and redifferentiation conditions on chondrogenic capacity of cultured chondrocytes. Tissue Eng 12:2435–2447PubMedGoogle Scholar
  62. 62.
    Lennon DP, Haynesworth SE, Young RG, Dennis JE, Caplan AI (1995) A chemically defined medium supports in vitro proliferation and maintains the osteochondral potential of rat marrow-derived mesenchymal stem cells. Exp Cell Res 219:211–222PubMedGoogle Scholar
  63. 63.
    Richardson SM, Walker RV, Parker S, Rhodes NP, Hunt JA, Freemont AJ, Hoyland JA (2006) Intervertebral disc cell-mediated mesenchymal stem cell differentiation. Stem Cells 24:707–716PubMedGoogle Scholar
  64. 64.
    Hayflick L (1965) The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 37:614–636PubMedGoogle Scholar
  65. 65.
    Shelton DN, Chang E, Whittier PS, Choi D, Funk WD (1999) Microarray analysis of replicative senescence. Curr Biol 9:939–945PubMedGoogle Scholar
  66. 66.
    Campisi J, d’Adda di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8:729–740PubMedGoogle Scholar
  67. 67.
    Wright KT, El Masri W, Osman A, Roberts S, Travedi J, Ashton BA, Johnson WEB (2008) The cell culture expansion of bone marrow stromal cells from humans with spinal cord injury: implications for future cell transplantation therapy. Spinal Cord 46:811–817PubMedGoogle Scholar
  68. 68.
    Schellenberg A, Stiehl T, Horn P, Joussen S, Pallua N, Ho AD, Wagner W (2012) Population dynamics of mesenchymal stromal cells during culture expansion. Cytotherapy 14:401–411PubMedGoogle Scholar
  69. 69.
    Martin I, Muraglia A, Campanile G, Cancedda R, Quarto R (2005) Fibroblast growth factor-2 supports ex vivo expansion and maintenance of osteogenic precursors from human bone marrow. Endocrinology 138:4456–4462Google Scholar
  70. 70.
    Li J, Pei M (2012) Cell senescence: a challenge in cartilage engineering and regeneration. Tissue Eng Part B Rev 18:270–287PubMedGoogle Scholar
  71. 71.
    Urban J, McMullin JF (1988) Swelling pressure of the lumbar intervertebral discs: influence of age, spinal level, composition, and degeneration. Spine 13:179–187PubMedGoogle Scholar
  72. 72.
    Bartels EM, Fairbank JCT, Winlove CP, Urban JPG (1998) Oxygen and lactate concentrations measured in vivo in the intervertebral discs of patients with scoliosis and back pain. Spine 23:1–8PubMedGoogle Scholar
  73. 73.
    Wuertz K, Godburn K, Iatridis JC (2009) MSC response to pH levels found in degenerating intervertebral discs. Biochem Biophys Res Commun 379:824–829PubMedCentralPubMedGoogle Scholar
  74. 74.
    Liang C, Li H, Tao Y, Zhou X, Li F, Chen G, Chen Q (2012) Responses of human adipose-derived mesenchymal stem cells to chemical microenvironment of the intervertebral disc. J Transl Med 10:49PubMedCentralPubMedGoogle Scholar
  75. 75.
    Wu MH, Urban JP, Cui ZF, Cui Z, Xu X (2007) Effect of extracellular pH on matrix synthesis by chondrocytes in 3D agarose gel. Biotechnol Prog 23:430–434PubMedGoogle Scholar
  76. 76.
    Khan AA, Surrao DC (2012) The importance of bicarbonate and nonbicarbonate buffer systems in batch and continuous flow bioreactors for articular cartilage tissue engineering. Tissue Eng Part C Methods 18:358–368PubMedGoogle Scholar
  77. 77.
    Razaq S, Wilkins RJ, Urban JPG (2003) The effect of extracellular pH on matrix turnover by cells of the bovine nucleus pulposus. Eur Spine J 12:341–349PubMedCentralPubMedGoogle Scholar
  78. 78.
    Wuertz K, Urban JP, Klasen J, Ignatius A, Wilke HJ, Claes L, Neidlinger-Wilke C (2007) Influence of extracellular osmolarity and mechanical stimulation on gene expression of intervertebral disc cells. J Orthop Res 25:1513–1522PubMedGoogle Scholar
  79. 79.
    Kitano T, Zerwekh JE, Usui U, Edwrads ML, Flicker PL, Mooney V (1993) Biochemical changes associated with symptomatic human intervertebral disk. Clin Orthop Relat Res 29:372–377Google Scholar
  80. 80.
    Stoyanov JV, Gantenbein-Ritter B, Bertolo A, Aebli N, Baur M, Alini M, Grad S (2011) Role of hypoxia and growth and differentiation factor-5 on differentiation of human mesenchymal stem cells towards intervertebral nucleus pulposus-like cells. Eur Cell Mater 21:533–547PubMedGoogle Scholar
  81. 81.
    Gantenbein-Ritter B, Benneker LM, Alini M, Grad S (2011) Differential response of human bone marrow stromal cells to either TGF-beta(1) or rhGDF-5. Eur Spine J 20:962–971PubMedCentralPubMedGoogle Scholar
  82. 82.
    MacLean JJ, Roughley PJ, Monsey RD, Alini M, Iatridis JC (2008) In vivo intervertebral disc remodelling: kinetics of mRNA expression in response to a single loading event. J Orthop Res 26:579–588PubMedCentralPubMedGoogle Scholar
  83. 83.
    Wilke H-J, Neef P, Caimi M, Hoogland T, Claes LE (1999) New in vivo measurements of pressures in the intervertebral disc in daily life. Spine 24:755–762PubMedGoogle Scholar
  84. 84.
    Nachemson A (1975) Towards a better understanding of low-back pain: a review of the mechanics of the lumbar disc. Rheumatol Rehabil 14:129–143PubMedGoogle Scholar
  85. 85.
    Huang AH, Farrell MJ, Mauck RL (2010) Mechanics and mechanobiology of mesenchymal stem cell-based engineered cartilage. J Biomech 43:128–136PubMedCentralPubMedGoogle Scholar
  86. 86.
    Kasra M, Goel V, Martin J, Wang ST, Choi W, Buckwalter J (2003) Effect of dynamic hydrostatic pressure on rabbit intervertebral disc cells. J Orthop Res 21:597–603PubMedGoogle Scholar
  87. 87.
    Elder BD, Athanasiou KA (2009) Hydrostatic pressure in articular cartilage tissue engineering: from chondrocytes to tissue regeneration. Tissue Eng Part B Rev 15:43–53PubMedCentralPubMedGoogle Scholar
  88. 88.
    Neidlinger-Wilke C, Mietsch A, Rinkler C, Wilke HJ, Ignatius A, Urban J (2012) Interactions of environmental conditions and mechanical loads have influence on matrix turnover by nucleus pulposus cells. J Orthop Res 30:112–121PubMedGoogle Scholar
  89. 89.
    Gerber BE (1997) Clinical context and pilot experience with autologous replantation of cultured disc tissue. In: Proceedings of 2nd ICRS, p 43Google Scholar
  90. 90.
    Centeno CJ, Schultz JR, Cheever M, Robinson B, Freeman M, Marasco W (2010) Safety and compilations reporting on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther 5:81–93PubMedGoogle Scholar
  91. 91.
    Yoshikawa T, Ueda Y, Miyazaki K, Koizumi M, Takakura Y (2010) Disc regeneration therapy using marrow mesenchymal cell transplantation: a report of two case studies. Spine 35:E475–E480PubMedGoogle Scholar
  92. 92.
    Orozco L, Soler R, Morera C, Alberca M, Sanchez A, Garcia-Sancho J (2011) Intervertebral disc repair by autologous mesenchymal bone marrow cells: a pilot study. Transplantation 92:822–828PubMedGoogle Scholar
  93. 93.
    Haufe S, Mork A (2006) Intradiscal injection of hematopoietic stem cells in an attempt to rejuvenate the intervertebral discs. Stem Cells Dev 15:136–137PubMedGoogle Scholar
  94. 94.
    Namba RS, Meuli M, Sullivan KM, Le AX, Adzick NS (1998) Spontaneous repair of superficial defects in articular cartilage in a fetal lamb model. J Bone Joint Surg Am 80:4–10PubMedGoogle Scholar
  95. 95.
    Hirt-Burri N, Ramelet AA, Raffoul W, de Buys RA, Scaletta C, Pioletti D, Applegate LA (2011) Biologicals and fetal cell therapy for wound and scar management. ISRN Dermatol 549870:1–16Google Scholar
  96. 96.
    Quintin A, Hirt-Burri N, Scaletta C, Schizas C, Pioletti DP, Applegate LA (2007) Consistency and safety of cell banks for research and clinical use: preliminary analysis of fetal skin banks. Cell Transpl 16:675–684Google Scholar
  97. 97.
    Quintin A, Schizas C, Scaletta C, Jaccoud S, Gerber S, Osterheld M-C, Juillerat L, Applegate LA, Pioletti DP (2009) Isolation and in vitro chondrogenic potential of human fetal spine cells. J Cell Mol Med 13:2559–2569PubMedGoogle Scholar
  98. 98.
    Son RR, Marquez-Curtis LA, Kucia M, Wycoczynski M, Turner AR, Ratajczak MZ, Janowska-Wieczorek A (2006) Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-MET axes and involves matrix metalloproteinases. Stem Cells 24:1254–1264PubMedGoogle Scholar
  99. 99.
    Kucia M, Wojakowski W, Reca R, Machalinski B, Gozdzik J, Majka M, Baran J, Ratajczak J, Ratajczak MZ (2006) The migration of bone marrow-derived non-hematopoietic tissue-committed stem cells is regulated in an SDF-1-, HGF-, and LIF-dependent manner. Arch Immunol Ther Exp (Warsz) 54:121–135Google Scholar
  100. 100.
    Zou C, Luo Q, Qin J, Shi Y, Yang L, Ju B, Song G (2012) Osteopontin promotes mesenchymal stem cell migration and lessens cell stiffness via integrin beta1, FAK, and ERK pathways. Cell Biochem Biophys 65(3):455–462Google Scholar
  101. 101.
    Jeong JH, Lee JH, Jin ES, Min JK, Jeon SR, Choi KH (2010) Regeneration of intervertebral discs in a rat disc degeneration model by implanted adipose-tissue-derived stromal cells. Acta Neurochir (Wien) 152:1771–1777Google Scholar
  102. 102.
    Gebhard H, Bowles R, Dyke J, Saleh T, Doty S, Bonassar L, Hartl R (2010) Total disc replacement using a tissue-engineered intervertebral disc in vivo: new animal model and initial results. Evid Based Spine Care J 1:62–66PubMedCentralPubMedGoogle Scholar
  103. 103.
    Huang B, Zhuang Y, Li CQ, Liu LT, Zhou Y (2011) Regeneration of the intervertebral disc with nucleus pulposus cell-seeded collagen II/hyaluronan/chondroitin-6-sulfate tri-copolymer constructs in a rabbit disc degeneration model. Spine (Phila Pa 1976) 36:2252–2259Google Scholar
  104. 104.
    Ruan DK, Xin H, Zhang C, Wang C, Xu C, Li C, He Q (2010) Experimental intervertebral disc regeneration with tissue-engineered composite in a canine model. Tissue Eng Part A 16:2381–2389PubMedGoogle Scholar
  105. 105.
    Omlor GW, Bertram H, Kleinschmidt K, Fischer J, Brohm K, Guehring T, Anton M, Richter W (2010) Methods to monitor distribution and metabolic activity of mesenchymal stem cells following in vivo injection into nucleotomized porcine intervertebral discs. Eur Spine J 19:601–612PubMedCentralPubMedGoogle Scholar
  106. 106.
    An HS, Masuda K (2006) Relevance of in vitro and in vivo models for intervertebral disc degeneration. J Bone Joint Surg Am 88(Suppl 2):88–94PubMedGoogle Scholar
  107. 107.
    DePuy Spine. A Clinical Trial to Evaluate the Safety, Tolerability and Preliminary Effectiveness of Single Administration Intradiscal rhGDF-5 for the Treatment of Early Stage Lumbar Disc Degeneration. Clinicaltrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01182337?term=nct01182337&rank=1.201220-12-0012
  108. 108.
    Sakai D, Nakamura Y, Nakai T, Mishima T, Kato S, Grad S, Alini M, Risbud MV, Chan D, Cheah KS, Yamamura K, Masuda K, Okano H, Ando K, Mochida J (2012) Exhaustion of nucleus pulposus progenitor cells with ageing and degeneration of the intervertebral disc. Nat Commun 3:1264PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Nevenka Kregar Velikonja
    • 1
    • 6
  • Jill Urban
    • 2
  • Mirjam Fröhlich
    • 1
  • Cornelia Neidlinger-Wilke
    • 3
  • Dimitris Kletsas
    • 4
  • Urska Potocar
    • 1
  • Sarah Turner
    • 5
  • Sally Roberts
    • 5
  1. 1.Educell Ltd.TrzinSlovenia
  2. 2.Department of Physiology, Anatomy and GeneticsUniversity of OxfordOxfordUK
  3. 3.Institute of Orthopaedic Research and BiomechanicsUniversity of UlmUlmGermany
  4. 4.Laboratory of Cell Proliferation and Ageing Institute of Biology NCSR “Demokritos”AthensGreece
  5. 5.Spinal Studies, Robert Jones and Agnes Hunt Orthopaedic Hospital and ISTMKeele UniversityShropshireUK
  6. 6.Faculty for Health Sciences Novo mestoNovo mestoSlovenia

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