Cell-based therapies for the regeneration of the intervertebral disc: promises and challenges
Keywords:
intervertebral disc, low back pain, cell-based therapy, gene therapy, senescenceAbstract
Intervertebral disc (IVD) degeneration (IDD) has been yet inextricably associated to the manifestation of low back pain, a major cause of disability with a vast socioeconomic impact worldwide. IDD treatment has been challenging given that IDD is characterized by a constellation of changes, major among them being the reduction in cell number and the modification of the cellular phenotype and function, ultimately contributing to tissue structural breakdown. As alternative options to the conservative and surgical approaches that only target IDD symptoms, injection of bioactive substances, gene therapy or cell transplantation have been attempted with some encouraging results even though no complete restoration of the injured tissue has been achieved thus far. In this short review we discuss the effect of the particular IVD environment (a combination of nutrients’ and oxygen deprivation, mechanical and oxidative stress, high osmolality and acidic pH) on several parameters of the physiology of the resident or implanted cells that should be taken under consideration for a successful regenerative intervention. The role of cells’ senescence in IVD physiology is also discussed as a putative novel therapeutic target for IDD. Deep understanding of the molecular alterations underlying IVD cells’ responses could lead to more effective IDD treatment modalities.
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3. Stranjalis, G., K. Tsamandouraki, D.E. Sakas, et al., Low back pain in a representative sample of Greek population: analysis according to personal and socioeconomic characteristics. Spine (Phila Pa 1976), 2004. 29(12): p. 1355-60; discussion 1361.
4. Vos, T., A.D. Flaxman, M. Naghavi, et al., Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet, 2012. 380(9859): p. 2163-96.
5. Manchikanti, L., V. Singh, F.J. Falco, et al., Epidemiology of low back pain in adults. Neuromodulation, 2014. 17 Suppl 2: p. 3-10.
6. Risbud, M.V., A. Guttapalli, T.T. Tsai, et al., Evidence for skeletal progenitor cells in the degenerate human intervertebral disc. Spine (Phila Pa 1976), 2007. 32(23): p. 2537-44.
7. Urban, J.P., The role of the physicochemical environment in determining disc cell behaviour. Biochem Soc Trans, 2002. 30(Pt 6): p. 858-64.
8. Urban, J.P. and J.F. McMullin, Swelling pressure of the inervertebral disc: influence of proteoglycan and collagen contents. Biorheology, 1985. 22(2): p. 145-57.
9. Nerlich, A.G., E.D. Schleicher, and N. Boos, 1997 Volvo Award winner in basic science studies. Immunohistologic markers for age-related changes of human lumbar intervertebral discs. Spine (Phila Pa 1976), 1997. 22(24): p. 2781-95.
10. Kletsas, D., Senescent cells in the intervertebral disc: numbers and mechanisms. Spine J, 2009. 9(8): p. 677-8.
11. Johnson, W.E., S.M. Eisenstein, and S. Roberts, Cell cluster formation in degenerate lumbar intervertebral discs is associated with increased disc cell proliferation. Connect Tissue Res, 2001. 42(3): p. 197-207.
12. Wang, S.Z., Y.F. Rui, J. Lu, et al., Cell and molecular biology of intervertebral disc degeneration: current understanding and implications for potential therapeutic strategies. Cell Prolif, 2014. 47(5): p. 381-90.
13. Mavrogonatou, E., H. Pratsinis, A. Papadopoulou, et al., Extracellular matrix alterations in senescent cells and their significance in tissue homeostasis. Matrix Biol, 2019. 75-76: p. 27-42.
14. Smith, L.J., L. Silverman, D. Sakai, et al., Advancing cell therapies for intervertebral disc regeneration from the lab to the clinic: Recommendations of the ORS spine section. JOR Spine, 2018. 1(4): p. e1036.
15. Colella, F., J.P. Garcia, M. Sorbona, et al., Drug delivery in intervertebral disc degeneration and osteoarthritis: Selecting the optimal platform for the delivery of disease-modifying agents. J Control Release, 2020.
16. Hanley, E.N., Jr., H.N. Herkowitz, J.S. Kirkpatrick, et al., Debating the value of spine surgery. J Bone Joint Surg Am, 2010. 92(5): p. 1293-304.
17. Clouet, J., M. Fusellier, A. Camus, et al., Intervertebral disc regeneration: From cell therapy to the development of novel bioinspired endogenous repair strategies. Adv Drug Deliv Rev, 2019. 146: p. 306-324.
18. Masuda, K., Biological repair of the degenerated intervertebral disc by the injection of growth factors. Eur Spine J, 2008. 17 Suppl 4(Suppl 4): p. 441-51.
19. Masuda, K., T.R. Oegema, Jr., and H.S. An, Growth factors and treatment of intervertebral disc degeneration. Spine (Phila Pa 1976), 2004. 29(23): p. 2757-69.
20. Pratsinis, H. and D. Kletsas, PDGF, bFGF and IGF-I stimulate the proliferation of intervertebral disc cells in vitro via the activation of the ERK and Akt signaling pathways. Eur Spine J, 2007. 16(11): p. 1858-66.
21. Pratsinis, H. and D. Kletsas, Growth factors in intervertebral disc homeostasis. Connect Tissue Res, 2008. 49(3): p. 273-6.
22. Pratsinis, H., V. Constantinou, K. Pavlakis, et al., Exogenous and autocrine growth factors stimulate human intervertebral disc cell proliferation via the ERK and Akt pathways. J Orthop Res, 2012. 30(6): p. 958-64.
23. Feng, C., H. Liu, Y. Yang, et al., Growth and differentiation factor-5 contributes to the structural and functional maintenance of the intervertebral disc. Cell Physiol Biochem, 2015. 35(1): p. 1-16.
24. Walsh, A.J., D.S. Bradford, and J.C. Lotz, In vivo growth factor treatment of degenerated intervertebral discs. Spine (Phila Pa 1976), 2004. 29(2): p. 156-63.
25. Akeda, K., H.S. An, R. Pichika, et al., Platelet-rich plasma (PRP) stimulates the extracellular matrix metabolism of porcine nucleus pulposus and anulus fibrosus cells cultured in alginate beads. Spine (Phila Pa 1976), 2006. 31(9): p. 959-66.
26. Gelalis, I.D., G. Christoforou, A. Charchanti, et al., Autologous platelet-rich plasma (PRP) effect on intervertebral disc restoration: an experimental rabbit model. Eur J Orthop Surg Traumatol, 2019. 29(3): p. 545-551.
27. Takeoka, Y., T. Yurube, and K. Nishida, Gene Therapy Approach for Intervertebral Disc Degeneration: An Update. Neurospine, 2020. 17(1): p. 3-14.
28. Sampara, P., R.R. Banala, S.K. Vemuri, et al., Understanding the molecular biology of intervertebral disc degeneration and potential gene therapy strategies for regeneration: a review. Gene Ther, 2018. 25(2): p. 67-82.
29. Somia, N. and I.M. Verma, Gene therapy: trials and tribulations. Nat Rev Genet, 2000. 1(2): p. 91-9.
30. Tripathy, S.K., H.B. Black, E. Goldwasser, et al., Immune responses to transgene-encoded proteins limit the stability of gene expression after injection of replication-defective adenovirus vectors. Nat Med, 1996. 2(5): p. 545-50.
31. Wallach, C.J., J.S. Kim, S. Sobajima, et al., Safety assessment of intradiscal gene transfer: a pilot study. Spine J, 2006. 6(2): p. 107-12.
32. Hwang, P.Y., L. Jing, J. Chen, et al., N-cadherin is Key to Expression of the Nucleus Pulposus Cell Phenotype under Selective Substrate Culture Conditions. Sci Rep, 2016. 6: p. 28038.
33. Farhang, N., M. Ginley-Hidinger, K.C. Berrett, et al., Lentiviral CRISPR Epigenome Editing of Inflammatory Receptors as a Gene Therapy Strategy for Disc Degeneration. Hum Gene Ther, 2019. 30(9): p. 1161-1175.
34. Vadalà, G., G.A. Sowa, and J.D. Kang, Gene therapy for disc degeneration. Expert Opin Biol Ther, 2007. 7(2): p. 185-96.
35. Kregar Velikonja, N., J. Urban, M. Fröhlich, et al., Cell sources for nucleus pulposus regeneration. Eur Spine J, 2014. 23 Suppl 3: p. S364-74.
36. Vadalà, G., F. Russo, L. Ambrosio, et al., Stem cells sources for intervertebral disc regeneration. World J Stem Cells, 2016. 8(5): p. 185-201.
37. Bron, J.L., L.A. Vonk, T.H. Smit, et al., Engineering alginate for intervertebral disc repair. J Mech Behav Biomed Mater, 2011. 4(7): p. 1196-205.
38. Pereira, D.R., J. Silva-Correia, J.M. Oliveira, et al., Hydrogels in acellular and cellular strategies for intervertebral disc regeneration. J Tissue Eng Regen Med, 2013. 7(2): p. 85-98.
39. Pratsinis, H. and D. Kletsas, Organotypic Cultures of Intervertebral Disc Cells: Responses to Growth Factors and Signaling Pathways Involved. Biomed Res Int, 2015. 2015: p. 427138.
40. Blanquer, S.B., D.W. Grijpma, and A.A. Poot, Delivery systems for the treatment of degenerated intervertebral discs. Adv Drug Deliv Rev, 2015. 84: p. 172-87.
41. Johnson, Z.I., Z.R. Schoepflin, H. Choi, et al., Disc in flames: Roles of TNF-α and IL-1β in intervertebral disc degeneration. Eur Cell Mater, 2015. 30: p. 104-16; discussion 116-7.
42. Wuertz, K., N. Vo, D. Kletsas, et al., Inflammatory and catabolic signalling in intervertebral discs: the roles of NF-κB and MAP kinases. Eur Cell Mater, 2012. 23: p. 103-19; discussion 119-20.
43. Hoyland, J.A., C. Le Maitre, and A.J. Freemont, Investigation of the role of IL-1 and TNF in matrix degradation in the intervertebral disc. Rheumatology (Oxford), 2008. 47(6): p. 809-14.
44. Mavrogonatou, E., M.T. Angelopoulou, and D. Kletsas, The catabolic effect of TNFα on bovine nucleus pulposus intervertebral disc cells and the restraining role of glucosamine sulfate in the TNFα-mediated up-regulation of MMP-3. J Orthop Res, 2014. 32(12): p. 1701-7.
45. Neidlinger-Wilke, C., F. Galbusera, H. Pratsinis, et al., Mechanical loading of the intervertebral disc: from the macroscopic to the cellular level. Eur Spine J, 2014. 23 Suppl 3: p. S333-43.
46. Pratsinis, H., A. Papadopoulou, C. Neidlinger-Wilke, et al., Cyclic tensile stress of human annulus fibrosus cells induces MAPK activation: involvement in proinflammatory gene expression. Osteoarthritis Cartilage, 2016. 24(4): p. 679-87.
47. Mavrogonatou, E., K. Papadimitriou, J.P. Urban, et al., Deficiency in the α1 subunit of Na+/K+-ATPase enhances the anti-proliferative effect of high osmolality in nucleus pulposus intervertebral disc cells. J Cell Physiol, 2015. 230(12): p. 3037-48.
48. Mavrogonatou, E. and D. Kletsas, High osmolality activates the G1 and G2 cell cycle checkpoints and affects the DNA integrity of nucleus pulposus intervertebral disc cells triggering an enhanced DNA repair response. DNA Repair (Amst), 2009. 8(8): p. 930-43.
49. Mavrogonatou, E. and D. Kletsas, Differential response of nucleus pulposus intervertebral disc cells to high salt, sorbitol, and urea. J Cell Physiol, 2012. 227(3): p. 1179-87.
50. Mavrogonatou, E. and D. Kletsas, Effect of varying osmotic conditions on the response of bovine nucleus pulposus cells to growth factors and the activation of the ERK and Akt pathways. J Orthop Res, 2010. 28(10): p. 1276-82.
51. Mavrogonatou, E. and D. Kletsas, The effect of glucosamine sulfate on the proliferative potential and glycosaminoglycan synthesis of nucleus pulposus intervertebral disc cells. Spine (Phila Pa 1976), 2013. 38(4): p. 308-14.
52. Nerlich, A.G., B.E. Bachmeier, E. Schleicher, et al., Immunomorphological analysis of RAGE receptor expression and NF-kappaB activation in tissue samples from normal and degenerated intervertebral discs of various ages. Ann N Y Acad Sci, 2007. 1096: p. 239-48.
53. Sivan, S.S., E. Tsitron, E. Wachtel, et al., Age-related accumulation of pentosidine in aggrecan and collagen from normal and degenerate human intervertebral discs. Biochem J, 2006. 399(1): p. 29-35.
54. Vo, N., L.J. Niedernhofer, L.A. Nasto, et al., An overview of underlying causes and animal models for the study of age-related degenerative disorders of the spine and synovial joints. J Orthop Res, 2013. 31(6): p. 831-7.
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2021-04-26
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Basic Science
