Skip to main content
Springer Nature Link
Log in

Cell sources for nucleus pulposus regeneration

  • Review article
  • Published:
European Spine Journal Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

References

  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 24:5–21

    CAS  PubMed  Google Scholar 

  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 30:2379–2387

    PubMed  Google Scholar 

  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 18:988–997

    CAS  PubMed  Google Scholar 

  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 28:2609–2620

    PubMed  Google Scholar 

  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 49:15–21

    PubMed  Google Scholar 

  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 430:219–226

    Google Scholar 

  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 9:363–374

    PubMed  Google Scholar 

  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. 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. Kandel R, Roberts S, Urban JPG (2008) Tissue engineering of the intervertebral disc. Eur Spine J 17(Suppl 4):480–491

    PubMed Central  PubMed  Google Scholar 

  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 42:465–477

    PubMed  Google Scholar 

  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) 33:1843–1849

    Google Scholar 

  13. Roughley PJ (2004) Biology of intervertebral disc aging and degeneration. Spine 29:2691–2699

    PubMed  Google Scholar 

  14. Peacock A (1951) Observations on the pre-natal development of the intervertebral disc in man. J Anat 85:260–274

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Walmsley R (1953) The development and growth of the intervertebral disc. Edinb Med J 60(8):341–364

    CAS  PubMed  Google Scholar 

  16. Hunter CJ, Matyas JR, Duncan NA (2004) Cytomorphology of notochordal and chondrocyte cells from the nucleus pulposus: a species comparison. J Anat 205:357–362

    PubMed Central  PubMed  Google Scholar 

  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 14:359–369

    CAS  PubMed  Google Scholar 

  18. Roberts S, Evans H, Trivedi J, Menage J (2006) Histology and pathology of the human intervertebral disc. J Bone Jt Surg 88-A:10–14

    Google Scholar 

  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 60:1026–1034

    Google Scholar 

  20. Risbud MV, Shapiro IM (2011) Notochordal cells in the adult intervertebral disc: new perspective on an old question. Crit Rev Eukaryot Gene Expr 21:29–41

    CAS  PubMed Central  PubMed  Google Scholar 

  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 62:3695–3705

    Google Scholar 

  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) 34:1448–1456

    Google Scholar 

  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:R24

    Google Scholar 

  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 19:1761–1770

    PubMed Central  PubMed  Google Scholar 

  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) 34:2338–2345

    Google Scholar 

  26. Drazin D, Rosner J, Avalos P, Acosta F (2012) Stem cell therapy for degenerative disc disease. Adv Orthop 2012:961052

    PubMed Central  PubMed  Google Scholar 

  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. 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 222:23–32

    CAS  PubMed  Google Scholar 

  29. Sakai D (2011) Stem cell regeneration of the intervertebral disk. Orthop Clin North Am 42:555–562

    PubMed  Google Scholar 

  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 16:2174–2182

    PubMed Central  PubMed  Google Scholar 

  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 18:416–423

    CAS  PubMed  Google Scholar 

  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 63:3876–3886

    CAS  Google Scholar 

  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:R22

    Google Scholar 

  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–S125

    Google Scholar 

  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 10:265–272

    PubMed  Google Scholar 

  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):804–814

    PubMed  Google Scholar 

  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) 32:2537–2544

    Google Scholar 

  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) 35:2259–2265

    Google Scholar 

  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 21:613–622

    PubMed Central  PubMed  Google Scholar 

  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 92:726–736

    CAS  PubMed  Google Scholar 

  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:E4

    PubMed  Google Scholar 

  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 6:348–355

    CAS  PubMed  Google Scholar 

  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 17:3045–3055

    CAS  PubMed Central  PubMed  Google Scholar 

  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 30:2743–2748

    PubMed  Google Scholar 

  45. Roberts S, Evans EH, Kletsas D, Jaffray DC, Eisenstein SM (2006) Senescence in human intervertebral discs. Eur Spine J 15:S312–S316

    PubMed  Google Scholar 

  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 26:618–621

    CAS  PubMed  Google Scholar 

  47. Brock M, Patt S, Mayer HM (1992) The form and structure of the extruded disc. Spine 17:1457–1461

    CAS  PubMed  Google Scholar 

  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 18:1761–1765

    Google Scholar 

  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 231:352–358

    PubMed  Google Scholar 

  50. Erwin WM, Inman RD (2006) Notochord cells regulate intervertebral disc chondrocyte proteoglycan production and cell proliferation. Spine (Phila Pa 1976) 31:1094–1099

    Google Scholar 

  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:R81

    CAS  Google Scholar 

  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):2067–2076

    CAS  PubMed  Google Scholar 

  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 35:1101–1108

    PubMed  Google Scholar 

  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 8:58–64

    CAS  PubMed  Google Scholar 

  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 120:113–130

    CAS  PubMed Central  PubMed  Google Scholar 

  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) 36:153–159

    Google Scholar 

  57. Baer PC, Geiger H (2012) Adipose-derived mesenchymal stromal/stem cells: tissue localization, characterization, and heterogeneity. Stem Cells Int 2012:812693

    PubMed Central  PubMed  Google Scholar 

  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 23:43–48

    PubMed Central  PubMed  Google Scholar 

  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–R170

    CAS  PubMed  Google Scholar 

  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 48:149–158

    CAS  PubMed  Google Scholar 

  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 12:2435–2447

    CAS  PubMed  Google Scholar 

  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 219:211–222

    CAS  PubMed  Google Scholar 

  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 24:707–716

    CAS  PubMed  Google Scholar 

  64. Hayflick L (1965) The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 37:614–636

    CAS  PubMed  Google Scholar 

  65. Shelton DN, Chang E, Whittier PS, Choi D, Funk WD (1999) Microarray analysis of replicative senescence. Curr Biol 9:939–945

    CAS  PubMed  Google Scholar 

  66. Campisi J, d’Adda di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8:729–740

    CAS  PubMed  Google Scholar 

  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 46:811–817

    CAS  PubMed  Google Scholar 

  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 14:401–411

    CAS  PubMed  Google Scholar 

  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 138:4456–4462

    Google Scholar 

  70. Li J, Pei M (2012) Cell senescence: a challenge in cartilage engineering and regeneration. Tissue Eng Part B Rev 18:270–287

    CAS  PubMed  Google Scholar 

  71. Urban J, McMullin JF (1988) Swelling pressure of the lumbar intervertebral discs: influence of age, spinal level, composition, and degeneration. Spine 13:179–187

    CAS  PubMed  Google Scholar 

  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 23:1–8

    CAS  PubMed  Google Scholar 

  73. Wuertz K, Godburn K, Iatridis JC (2009) MSC response to pH levels found in degenerating intervertebral discs. Biochem Biophys Res Commun 379:824–829

    CAS  PubMed Central  PubMed  Google Scholar 

  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 10:49

    CAS  PubMed Central  PubMed  Google Scholar 

  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 23:430–434

    CAS  PubMed  Google Scholar 

  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 18:358–368

    CAS  PubMed  Google Scholar 

  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 12:341–349

    PubMed Central  PubMed  Google Scholar 

  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 25:1513–1522

    CAS  PubMed  Google Scholar 

  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 29:372–377

    Google Scholar 

  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 21:533–547

    CAS  PubMed  Google Scholar 

  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 20:962–971

    PubMed Central  PubMed  Google Scholar 

  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 26:579–588

    CAS  PubMed Central  PubMed  Google Scholar 

  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 24:755–762

    CAS  PubMed  Google Scholar 

  84. Nachemson A (1975) Towards a better understanding of low-back pain: a review of the mechanics of the lumbar disc. Rheumatol Rehabil 14:129–143

    CAS  PubMed  Google Scholar 

  85. Huang AH, Farrell MJ, Mauck RL (2010) Mechanics and mechanobiology of mesenchymal stem cell-based engineered cartilage. J Biomech 43:128–136

    PubMed Central  PubMed  Google Scholar 

  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 21:597–603

    PubMed  Google Scholar 

  87. Elder BD, Athanasiou KA (2009) Hydrostatic pressure in articular cartilage tissue engineering: from chondrocytes to tissue regeneration. Tissue Eng Part B Rev 15:43–53

    CAS  PubMed Central  PubMed  Google Scholar 

  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 30:112–121

    PubMed  Google Scholar 

  89. Gerber BE (1997) Clinical context and pilot experience with autologous replantation of cultured disc tissue. In: Proceedings of 2nd ICRS, p 43

  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 5:81–93

    CAS  PubMed  Google Scholar 

  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–E480

    PubMed  Google Scholar 

  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 92:822–828

    PubMed  Google Scholar 

  93. Haufe S, Mork A (2006) Intradiscal injection of hematopoietic stem cells in an attempt to rejuvenate the intervertebral discs. Stem Cells Dev 15:136–137

    PubMed  Google Scholar 

  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 80:4–10

    CAS  PubMed  Google Scholar 

  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 549870:1–16

    Google Scholar 

  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 16:675–684

    Google Scholar 

  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 13:2559–2569

    PubMed  Google Scholar 

  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 24:1254–1264

    CAS  PubMed  Google Scholar 

  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) 54:121–135

    CAS  Google Scholar 

  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):455–462

    Google Scholar 

  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) 152:1771–1777

    Google Scholar 

  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 1:62–66

    PubMed Central  PubMed  Google Scholar 

  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) 36:2252–2259

    Google Scholar 

  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 16:2381–2389

    CAS  PubMed  Google Scholar 

  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 19:601–612

    CAS  PubMed Central  PubMed  Google Scholar 

  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):88–94

    PubMed  Google Scholar 

  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. 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 3:1264

    PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

We are grateful for support for funding towards this research from the European Community’s Seventh Framework Programme (FP7, 2007–2013) under Grant Agreement No. HEALTH-F2-2008-201626 (Genodisc) and FP7-People-2007-2-2-ERG (Grant Agreement 224834), to Slovenian Research agency (grant agreement L3-2351) and to Dr. Michelle Kumin for editorial assistance.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Educell Ltd., Prevale 9, Trzin, Slovenia

    Nevenka Kregar Velikonja, Mirjam Fröhlich & Urska Potocar

  2. Department of Physiology, Anatomy and Genetics, University of Oxford, Le Gros Clark Building South Parks Road, Oxford, OX1 3QX, UK

    Jill Urban

  3. Institute of Orthopaedic Research and Biomechanics, University of Ulm, Helmholtzstraße 14, 89081, Ulm, Germany

    Cornelia Neidlinger-Wilke

  4. Laboratory of Cell Proliferation and Ageing Institute of Biology NCSR “Demokritos”, 153 10, Athens, Greece

    Dimitris Kletsas

  5. Spinal Studies, Robert Jones and Agnes Hunt Orthopaedic Hospital and ISTM, Keele University, Oswestry, Shropshire, SY10 7AG, UK

    Sarah Turner & Sally Roberts

  6. Faculty for Health Sciences Novo mesto, Na Loko 2, Novo mesto, Slovenia

    Nevenka Kregar Velikonja

Authors
  1. Nevenka Kregar Velikonja
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Jill Urban
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Mirjam Fröhlich
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Cornelia Neidlinger-Wilke
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Dimitris Kletsas
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Urska Potocar
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Sarah Turner
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Sally Roberts
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Nevenka Kregar Velikonja.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kregar Velikonja, N., Urban, J., Fröhlich, M. et al. Cell sources for nucleus pulposus regeneration. Eur Spine J 23 (Suppl 3), 364–374 (2014). https://doi.org/10.1007/s00586-013-3106-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00586-013-3106-9

Keywords