Advertisement

Use of Stem Cells in Spinal Treatments

  • S. Mohammed Karim
  • Shuanhu Zhou
  • James D. KangEmail author
Chapter

Abstract

The intervertebral disc (IVD) is a complex anatomic structure consisting of a nucleus pulposus (NP), annulus fibrosis (AF), and cartilaginous vertebral end plates. Like all human tissue, these structures undergo age-related degenerative changes termed IVD degeneration (IVDD). In this process, the cell biology of the IVD components is altered. The NP’s ability to synthesize its extracellular matrix components is disturbed, and the AF becomes susceptible to tearing, both of which alter the IVD’s biomechanical properties. As the IVD degenerates, patients may develop discogenic back pain from the inflammatory milieu of IVDD. The altered spinal biomechanics may also contribute to the development of facet joint arthropathy—another source of back pain. The failing AF may allow NP material to herniate resulting in nerve root and/or spinal cord compression. The hope of stem cell treatments is to use pluripotent cells to differentiate into and regenerate normally functional IVD components in order to arrest and/or reverse the degenerative changes of IVDD. Some evidence of IVD regeneration has been seen in both animal studies and small clinical trials. In addition to IVD regeneration, the pluripotent nature of stem cells also lends them to facilitate spinal fusion by differentiating into osteoblasts and creating a biologic environment more favorable for fusion. Animal studies and clinical trials have also shown some promise in facilitating spinal fusion. In general, more clinical data are needed to ascertain whether stem cells may be effective in the treatment of IVD degeneration and in positively influencing spinal fusion procedures.

Keywords

Intervertebral disc degeneration Stem cell therapy Nucleus pulposus Disc regeneration Mesenchymal stem cells 

References

  1. 1.
    Khan AN, Jacobsen HE, Khan J, Filippi CG, Levine M, Lehman RA Jr, et al. Inflammatory biomarkers of low back pain and disc degeneration: a review. Ann N Y Acad Sci. 2017;1410(1):68–84.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Henry N, Clouet J, Le Bideau J, Le Visage C, Guicheux J. Innovative strategies for intervertebral disc regenerative medicine: from cell therapies to multiscale delivery systems. Biotechnol Adv. 2018;36(1):281–94.PubMedCrossRefGoogle Scholar
  3. 3.
    Silagi ES, Shapiro IM, Risbud MV. Glycosaminoglycan synthesis in the nucleus pulposus: Dysregulation and the pathogenesis of disc disease. Matrix Biol. 2018;71–72:368–79.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Newell N, Little JP, Christou A, Adams MA, Adam CJ, Masouros SD. Biomechanics of the human intervertebral disc: a review of testing techniques and results. J Mech Behav Biomed Mater. 2017;69:420–34.PubMedCrossRefGoogle Scholar
  5. 5.
    Barr JS. Intervertebral disk lesions as cause of sciatica. Br Med J. 1938;2(4067):1247–74.2.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Dowdell J, Erwin M, Choma T, Vaccaro A, Iatridis J, Cho SK. Intervertebral disk degeneration and repair. Neurosurgery. 2017;80(3s):S46–s54.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Eyre DR, Muir H. Types I and II collagens in intervertebral disc. Interchanging radial distributions in annulus fibrosus. Biochem J. 1976;157(1):267–70.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Sivan SS, Hayes AJ, Wachtel E, Caterson B, Merkher Y, Maroudas A, et al. Biochemical composition and turnover of the extracellular matrix of the normal and degenerate intervertebral disc. Eur Spine J. 2014;23(Suppl 3):S344–53.PubMedCrossRefGoogle Scholar
  9. 9.
    Bushell GR, Ghosh P, Taylor TF, Akeson WH. Proteoglycan chemistry of the intervertebral disks. Clin Orthop Relat Res. 1977;129:115–23.CrossRefGoogle Scholar
  10. 10.
    Ghosh P, Bushell GR, Taylor TF, Akeson WH. Collagens, elastin and noncollagenous protein of the intervertebral disk. Clin Orthop Relat Res. 1977;129:124–32.CrossRefGoogle Scholar
  11. 11.
    Aguiar DJ, Johnson SL, Oegema TR. Notochordal cells interact with nucleus pulposus cells: regulation of proteoglycan synthesis. Exp Cell Res. 1999;246(1):129–37.PubMedCrossRefGoogle Scholar
  12. 12.
    Kerr GJ, Veras MA, Kim MK, Seguin CA. Decoding the intervertebral disc: unravelling the complexities of cell phenotypes and pathways associated with degeneration and mechanotransduction. Semin Cell Dev Biol. 2017;62:94–103.PubMedCrossRefGoogle Scholar
  13. 13.
    Tavakoli J, Elliott DM, Costi JJ. Structure and mechanical function of the inter-lamellar matrix of the annulus fibrosus in the disc. J Orthop Res. 2016;34(8):1307–15.PubMedCrossRefGoogle Scholar
  14. 14.
    Kadow T, Sowa G, Vo N, Kang JD. Molecular basis of intervertebral disc degeneration and herniations: what are the important translational questions? Clin Orthop Relat Res. 2015;473(6):1903–12.PubMedCrossRefGoogle Scholar
  15. 15.
    Boos N, Weissbach S, Rohrbach H, Weiler C, Spratt KF, Nerlich AG. Classification of age-related changes in lumbar intervertebral discs: 2002 Volvo Award in basic science. Spine. 2002;27(23):2631–44.PubMedCrossRefGoogle Scholar
  16. 16.
    Vergroesen PP, Kingma I, Emanuel KS, Hoogendoorn RJ, Welting TJ, van Royen BJ, et al. Mechanics and biology in intervertebral disc degeneration: a vicious circle. Osteoarthr Cartil. 2015;23(7):1057–70.PubMedCrossRefGoogle Scholar
  17. 17.
    Jim B, Steffen T, Moir J, Roughley P, Haglund L. Development of an intact intervertebral disc organ culture system in which degeneration can be induced as a prelude to studying repair potential. Eur Spine J. 2011;20(8):1244–54.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Nguyen C, Boutron I, Baron G, Sanchez K, Palazzo C, Benchimol R, et al. Intradiscal glucocorticoid injection for patients with chronic low back pain associated with ctive discopathy: a randomized trial. Ann Intern Med. 2017;166(8):547–56.PubMedCrossRefGoogle Scholar
  19. 19.
    Inoue N, Espinoza Orias AA. Biomechanics of intervertebral disk degeneration. Orthop Clin North Am. 2011;42(4):487–99, vii.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Iorio JA, Jakoi AM, Singla A. Biomechanics of degenerative spinal disorders. Asian Spine J. 2016;10(2):377–84.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Pattappa G, Li Z, Peroglio M, Wismer N, Alini M, Grad S. Diversity of intervertebral disc cells: phenotype and function. J Anat. 2012;221:480–96.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Sakai D, Andersson GB. Stem cell therapy for intervertebral disc regeneration: obstacles and solutions. Nat Rev Rheumatol. 2015;11:243–56.PubMedCrossRefGoogle Scholar
  23. 23.
    Li Z, Peroglio M, Alini M, Grad S. Potential and limitations of intervertebral disc endogenous repair. Curr Stem Cell Res Ther. 2015;10:329–38.PubMedCrossRefGoogle Scholar
  24. 24.
    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. Exhaustion of nucleus pulposus progenitor cells with ageing and degeneration of the intervertebral disc. Nat Commun. 2012;3:1264.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Vadalà G, Russo F, Ambrosio L, Loppini M, Denaro V. Stem cells sources for intervertebral disc regeneration. World J Stem Cells. 2016;8:185–201.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Zhou S. From bone to brain: human skeletal stem cell therapy for stroke. Cent Nerv Syst Agents Med Chem. 2011;11:157–63.PubMedCrossRefGoogle Scholar
  27. 27.
    Schipani E, Kronenberg HM. Adult mesenchymal stem cells. In: Stem book. Cambridge: Harvard Stem Cell Institute; 2009.Google Scholar
  28. 28.
    Ciuffi S, Zonefrati R, Brandi ML. Adipose stem cells for bone tissue repair. Clin Cases Miner Bone Metab. 2017;14:217–26.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Steinert AF, Rackwitz L, Gilbert F, Nöth U, Tuan RS. Concise review: the clinical application of mesenchymal stem cells for musculoskeletal regeneration: current status and perspectives. Stem Cells Trans Med. 2012;1:237–47.CrossRefGoogle Scholar
  30. 30.
    Ghasroldasht MM, Irfan-Maqsood M, Matin MM, Bidkhori HR, Naderi-Meshkin H, Moradi A, Bahrami AR. Mesenchymal stem cell based therapy for osteo-diseases. Cell Biol Int. 2014;38:1081–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Evans CH. Advances in regenerative orthopedics. Mayo Clin Proc. 2013;88:1323–39.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Berebichez-Fridman R, Gómez-García R, Granados-Montiel J, Berebichez-Fastlicht E, Olivos-Meza A, Granados J, Velasquillo C, Ibarra C. The holy grail of orthopedic surgery: mesenchymal stem cells-their current uses and potential applications. Stem Cells Int. 2017;2017:2638305.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Xie L, Wang X, Zhou S. Mesenchymal stem cells and cartilage regeneration in traumatic and osteoarthritic cartilage defects. J Stem Cell Res Regen Med. 2014;1(1):002.Google Scholar
  34. 34.
    Risbud MV, Shapiro IM, Vaccaro AR, Albert TJ. Stem cell regeneration of the nucleus pulposus. Spine J. 2004;4:348S–53S.PubMedCrossRefGoogle Scholar
  35. 35.
    Bertolo A, Mehr M, Aebli N, Baur M, Ferguson SJ, Stoyanov JV. Influence of different commercial scaffolds on the in vitro differentiation of human mesenchymal stem cells to nucleus pulposus-like cells. Eur Spine J. 2012;21(Suppl 6):S826–38.PubMedCrossRefGoogle Scholar
  36. 36.
    Clarke LE, McConnell JC, Sherratt MJ, Derby B, Richardson SM, Hoyland JA. Growth differentiation factor 6 and transforming growth factor-beta differentially mediate mesenchymal stem cell differentiation, composition, and micromechanical properties of nucleus pulposus constructs. Arthritis Res Ther. 2014;16:R67.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Steck E, Bertram H, Abel R, Chen B, Winter A, Richter W. Induction of intervertebral disc-like cells from adult mesenchymal stem cells. Stem Cells. 2005;23:403–11.PubMedCrossRefGoogle Scholar
  38. 38.
    Nesti LJ, Li WJ, Shanti RM, Jiang YJ, Jackson W, Freedman BA, Kuklo TR, Giuliani JR, Tuan RS. Intervertebral disc tissue engineering using a novel hyaluronic acid-nanofibrous scaffold (HANFS) amalgam. Tissue Eng Part A. 2008;14:1527–37.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Handley C, Goldschlager T, Oehme D, Ghosh P, Jenkin G. Mesenchymal stem cell tracking in the intervertebral disc. World J Stem Cells. 2015 Jan 26;7(1):65–74.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Sobajima S, Vadala G, Shimer A, Kim JS, Gilbertson LG, Kang JD. Feasibility of a stem cell therapy for intervertebral disc degeneration. Spine J. 2008;8:888–96.PubMedCrossRefGoogle Scholar
  41. 41.
    Yang F, Leung VY, Luk KD, Chan D, Cheung KM. Mesenchymal stem cells arrest intervertebral disc degeneration through chondrocytic differentiation and stimulation of endogenous cells. Mol Ther. 2009;17:1959–66.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Barczewska M, Wojtkiewicz J, Habich A, Janowski M, Adamiak Z, Holak P, Matyjasik H, Bulte JW, Maksymowicz W, Walczak P. MR monitoring of minimally invasive delivery of mesenchymal stem cells into the porcine intervertebral disc. PLoS One. 2013;8(9):e74658.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Richardson SM, Kalamegam G, Pushparaj PN, Matta C, Memic A, Khademhosseini A, Mobasheri R, Poletti FL, Hoyland JA, Mobasheri A. Mesenchymal stem cells in regenerative medicine: focus on articular cartilage and intervertebral disc regeneration. Methods. 2016;99:69–80.PubMedCrossRefGoogle Scholar
  44. 44.
    Acosta FL Jr, Lotz J, Ames CP. The potential role of mesenchymal stem cell therapy for intervertebral disc degeneration: a critical overview. Neurosurg Focus. 2005;19:E4.PubMedCrossRefGoogle Scholar
  45. 45.
    Atesok K, Fu FH, Sekiya I, Stolzing A, Ochi M, Rodeo SA. Stem cells in degenerative orthopaedic pathologies: effects of aging on therapeutic potential. Knee Surg Sports Traumatol Arthrosc. 2017;25:626–36.PubMedCrossRefGoogle Scholar
  46. 46.
    Noriega DC, Ardura F, Hernández-Ramajo R, Martín-Ferrero MÁ, Sánchez-Lite I, Toribio B, Alberca M, García V, Moraleda JM, Sánchez A, García-Sancho J. Intervertebral disc repair by allogeneic mesenchymal bone marrow cells: a randomized controlled trial. Transplantation. 2017;101:1945–51.PubMedCrossRefGoogle Scholar
  47. 47.
    Orozco L, Soler R, Morera C, Alberca M, Sánchez A, García-Sancho J. Intervertebral disc repair by autologous mesenchymal bone marrow cells: a pilot study. Transplantation. 2011;92:822–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Comella K, Silbert R, Parlo M. Effects of the intradiscal implantation of stromal vascular fraction plus platelet rich plasma in patients with degenerative disc disease. J Transl Med. 2017;15:12.PubMedCrossRefGoogle Scholar
  49. 49.
    Pettine KA, Murphy MB, Suzuki RK, Sand TT. Percutaneous injection of autologous bone marrow concentrate cells significantly reduces lumbar discogenic pain through 12 months. Stem Cells. 2015;33:146–56.PubMedCrossRefGoogle Scholar
  50. 50.
    Autologous adipose tissue derived mesenchymal stem cells transplantation in patient with lumbar intervertebral disc degeneration. https://clinicaltrials.gov/ct2/show/NCT01643681.
  51. 51.
    Safety and preliminary efficacy study of Mesenchymal Precursor Cells (MPCs) in subjects with lumbar back pain. https://clinicaltrials.gov/ct2/show/NCT01290367.
  52. 52.
    Human autograft mesenchymal stem cell mediated stabilization of the degenerative lumbar spine. https://clinicaltrials.gov/ct2/show/NCT02529566.
  53. 53.
    Zhou S, Greenberger JS, Epperly MW, Goff JP, Adler C, Leboff MS, Glowacki J. Age-related intrinsic changes in human bone-marrow-derived mesenchymal stem cells and their differentiation to osteoblasts. Aging Cell. 2008;7:335–43.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Zhou S, Glowacki J, Kim SW, Hahne J, Geng S, Mueller SM, Shen L, Bleiberg I, LeBoff MS. Clinical characteristics influence in vitro action of 1,25-dihydroxyvitamin D(3) in human marrow stromal cells. J Bone Miner Res. 2012;27:1992–2000.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Zhou S, Glowacki J. Chronic kidney disease and vitamin D metabolism in human bone marrow-derived MSCs. Ann N Y Acad Sci. 2017;1402:43–55.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Liu K, Chen Z, Luo XW, Song GQ, Wang P, Li XD, Zhao M, Han XW, Bai YG, Yang ZL, Feng G. Determination of the potential of induced pluripotent stem cells to differentiate into mouse nucleus pulposus cells in vitro. Genet Mol Res. 2015;14:12394–405.PubMedCrossRefGoogle Scholar
  57. 57.
    Chen J, Lee EJ, Jing L, Christoforou N, Leong KW, Setton LA. Differentiation of mouse induced pluripotent stem cells (iPSCs) into nucleus pulposus-like cells in vitro. PLoS One. 2013;8:e75548.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Liu Y, Fu S, Rahaman MN, Mao JJ, Bal BS. Native nucleus pulposus tissue matrix promotes notochordal differentiation of human induced pluripotent stem cells with potential for treating intervertebral disc degeneration. J Biomed Mater Res A. 2015;103:1053–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Liu Y, Rahaman MN, Bal BS. Modulating notochordal differentiation of human induced pluripotent stem cells using natural nucleus pulposus tissue matrix. PLoS One. 2014;9:e100885.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Salamanna F, Sartori M, Barbanti Brodano G, Griffoni C, Martini L, Boriani S, Fini M. Mesenchymal stem cells for the treatment of spinal arthrodesis: from preclinical research to clinical scenario. Stem Cells Int. 2017;2017:3537094.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • S. Mohammed Karim
    • 1
  • Shuanhu Zhou
    • 2
  • James D. Kang
    • 2
    Email author
  1. 1.Department of Orthopaedic SurgeryBrigham and Women’s HospitalBostonUSA
  2. 2.Department of Orthopaedic SurgeryBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA

Personalised recommendations