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  • Review Article
  • Published:

Cell-based strategies for IVD repair: clinical progress and translational obstacles

Nature Reviews Rheumatology volume 17, pages 158–175 (2021)Cite this article

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Abstract

Intervertebral disc (IVD) degeneration is a major cause of low back pain, a prevalent and chronic condition that has a striking effect on quality of life. Currently, no approved pharmacological interventions or therapies are available that prevent the progressive destruction of the IVD; however, regenerative strategies are emerging that aim to modify the disease. Progress has been made in defining promising new treatments for disc disease, but considerable challenges remain along the entire translational spectrum, from understanding disease mechanism to useful interpretation of clinical trials, which make it difficult to achieve a unified understanding. These challenges include: an incomplete appreciation of the mechanisms of disc degeneration; a lack of standardized approaches in preclinical testing; in the context of cell therapy, a distinct lack of cohesion regarding the cell types being tested, the tissue source, expansion conditions and dose; the absence of guidelines regarding disease classification and patient stratification for clinical trial inclusion; and an incomplete understanding of the mechanisms underpinning therapeutic responses to cell delivery. This Review discusses current approaches to disc regeneration, with a particular focus on cell-based therapeutic strategies, including ongoing challenges, and attempts to provide a framework to interpret current data and guide future investigational studies.

Key points

  • Intervertebral disc degeneration is a notable contributing factor to the incidence of low back pain.

  • No pharmacological intervention, biologic therapy or procedure is approved for the prevention of disc degeneration; cell-based therapies are one approach currently being explored for promoting disc regeneration.

  • Clinical trials investigating cell-based therapies are underway but are often poorly designed, with low patient numbers and an absence of appropriate controls.

  • The broad range of disparate interventions relating to cell type, tissue source, expansion conditions, dose and delivery systems make it difficult to achieve unambiguous interpretation of results.

  • Better imaging and biochemical diagnostics are needed to inform patient stratification protocols to identify cohorts of patients who would most benefit from cell therapy.

  • Potential mechanisms of action of cell therapies have been proposed, including secretion of bioactive molecules, apoptosis and transfer of extracellular vesicles; however, concrete mechanistic evidence is lacking.

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Fig. 1: The intervertebral disc in health and disease.
Fig. 2: Potential mechanisms underlying mesenchymal stem cell-mediated repair.

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References

  1. Hoy, D. et al. The global burden of low back pain: estimates from the Global Burden of Disease 2010 study. Ann. Rheum. Dis. 73, 968–974 (2014).

    PubMed  Google Scholar 

  2. Dagenais, S., Caro, J. & Haldeman, S. A systematic review of low back pain cost of illness studies in the United States and internationally. Spine J. 8, 8–20 (2008).

    PubMed  Google Scholar 

  3. Duthey, B. Priority Medicines for Europe and the World, 2013 update. Background Paper 6.24: Low back pain. (WHO, 2013).

  4. Katz, J. N. Lumbar disc disorders and low-back pain: socioeconomic factors and consequences. J. Bone Joint Surg. 88, 21–24 (2006).

    PubMed  Google Scholar 

  5. Guo, H. R., Tanaka, S., Halperin, W. E. & Cameron, L. L. Back pain prevalence in US industry and estimates of lost workdays. Am. J. Public Health 89, 1029–1035 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Hartvigsen, J. et al. What low back pain is and why we need to pay attention. Lancet 391, 2356–2367 (2018).

    PubMed  Google Scholar 

  7. Buchbinder, R. et al. Low back pain: a call for action. Lancet 391, 2384–2388 (2018).

    PubMed  Google Scholar 

  8. Foster, N. E. et al. Prevention and treatment of low back pain: evidence, challenges, and promising directions. Lancet 391, 2368–2383 (2018).

    PubMed  Google Scholar 

  9. Luoma, K. et al. Low back pain in relation to lumbar disc degeneration. Spine 25, 487–492 (2000).

    CAS  PubMed  Google Scholar 

  10. Hoy, D. G. et al. Reflecting on the global burden of musculoskeletal conditions: lessons learnt from the Global Burden of Disease 2010 study and the next steps forward. Ann. Rheum. Dis. 74, 4–7 (2015).

    PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Risbud, M. V. & Shapiro, I. M. Notochordal cells in the adult intervertebral disc: new perspective on an old question. Crit. Rev. Eukaryot. Gene Expr. 21, 29–41 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Trout, J. J., Buckwalter, J. A., Moore, K. C. & Landas, S. K. Ultrastructure of the human intervertebral disc. I. Changes in notochordal cells with age. Tissue Cell 14, 359–369 (1982).

    CAS  PubMed  Google Scholar 

  14. Trout, J. J., Buckwalter, J. A. & Moore, K. C. Ultrastructure of the human intervertebral disc: II. Cells of the nucleus pulposus. Anat. Rec. 204, 307–314 (1982).

    CAS  PubMed  Google Scholar 

  15. Hunter, C. J., Matyas, J. R. & Duncan, N. A. The notochordal cell in the nucleus pulposus: a review in the context of tissue engineering. Tissue Eng. 9, 667–677 (2003).

    CAS  PubMed  Google Scholar 

  16. Roberts, S. Disc morphology in health and disease. Biochem. Soc. Trans. 30, 864–869 (2002).

    CAS  PubMed  Google Scholar 

  17. Smolders, L. A. et al. Intervertebral disc degeneration in the dog. Part 2: chondrodystrophic and non-chondrodystrophic breeds. Vet. J. 195, 292–299 (2013).

    PubMed  Google Scholar 

  18. Li, S. W. et al. Transgenic mice with targeted inactivation of the Col2α1 gene for collagen II develop a skeleton with membranous and periosteal bone but no endochondral bone. Genes Dev. 9, 2821–2830 (1995).

    CAS  PubMed  Google Scholar 

  19. Kimura, T. et al. Progressive degeneration of articular cartilage and intervertebral discs. An experimental study in transgenic mice bearing a type IX collagen mutation. Int. Orthop. 20, 177–181 (1996).

    PubMed  Google Scholar 

  20. Annunen, S. et al. An allele of COL9A2 associated with intervertebral disc disease. Science 285, 409–412 (1999).

    CAS  PubMed  Google Scholar 

  21. Kawaguchi, Y. et al. The association of lumbar disc disease with vitamin-D receptor gene polymorphism. J. Bone Joint Surg. Am. 84, 2022–2028 (2002).

    PubMed  Google Scholar 

  22. Ala-Kokko, L. Genetic risk factors for lumbar disc disease. Ann. Med. 34, 42–47 (2002).

    CAS  PubMed  Google Scholar 

  23. Noponen-Hietala, N. et al. Genetic variations in IL6 associate with intervertebral disc disease characterized by sciatica. Pain 114, 186–194 (2005).

    CAS  PubMed  Google Scholar 

  24. Maroudas, A., Stockwell, R. A., Nachemson, A. & Urban, J. Factors involved in the nutrition of the human lumbar intervertebral disc: cellularity and diffusion of glucose in vitro. J. Anat. 120, 113–130 (1975).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Horner, H. A. & Urban, J. P. 2001 Volvo Award Winner in Basic Science Studies: Effect of nutrient supply on the viability of cells from the nucleus pulposus of the intervertebral disc. Spine 26, 2543–2549 (2001).

    CAS  PubMed  Google Scholar 

  26. Urban, J. P., Smith, S. & Fairbank, J. C. Nutrition of the intervertebral disc. Spine 29, 2700–2709 (2004).

    PubMed  Google Scholar 

  27. Roberts, S., Evans, E. H., Kletsas, D., Jaffray, D. C. & Eisenstein, S. M. Senescence in human intervertebral discs. Eur. Spine J. 15, S312–S316 (2006).

    PubMed  Google Scholar 

  28. Le Maitre, C. L., Freemont, A. J. & Hoyland, J. A. Accelerated cellular senescence in degenerate intervertebral discs: a possible role in the pathogenesis of intervertebral disc degeneration. Arthritis Res. Ther. 9, R45 (2007).

    PubMed  PubMed Central  Google Scholar 

  29. Gruber, H. E., Ingram, J. A., Norton, H. J. & Hanley, E. N. Jr. Senescence in cells of the aging and degenerating intervertebral disc: immunolocalization of senescence-associated β-galactosidase in human and sand rat discs. Spine 32, 321–327 (2007).

    PubMed  Google Scholar 

  30. Le Maitre, C. L., Hoyland, J. A. & Freemont, A. J. Catabolic cytokine expression in degenerate and herniated human intervertebral discs: IL-1β and TNFα expression profile. Arthritis Res. Ther. 9, R77 (2007).

    PubMed  PubMed Central  Google Scholar 

  31. Le Maitre, C. L., Pockert, A., Buttle, D. J., Freemont, A. J. & Hoyland, J. A. Matrix synthesis and degradation in human intervertebral disc degeneration. Biochem. Soc. Trans. 35, 652–655 (2007).

    PubMed  Google Scholar 

  32. Hoyland, J. A., Le Maitre, C. & Freemont, A. J. Investigation of the role of IL-1 and TNF in matrix degradation in the intervertebral disc. Rheumatology 47, 809–814 (2008).

    CAS  PubMed  Google Scholar 

  33. Phillips, K. L. et al. The cytokine and chemokine expression profile of nucleus pulposus cells: implications for degeneration and regeneration of the intervertebral disc. Arthritis Res. Ther. 15, R213 (2013).

    PubMed  PubMed Central  Google Scholar 

  34. Purmessur, D. et al. A role for TNFα in intervertebral disc degeneration: a non-recoverable catabolic shift. Biochem. Biophys. Res. Commun. 433, 151–156 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Phillips, K. L. et al. Potential roles of cytokines and chemokines in human intervertebral disc degeneration: interleukin-1 is a master regulator of catabolic processes. Osteoarthritis Cartilage 23, 1165–1177 (2015).

    CAS  PubMed  Google Scholar 

  36. Gorth, D. J., Shapiro, I. M. & Risbud, M. V. Transgenic mice overexpressing human TNF-α experience early onset spontaneous intervertebral disc herniation in the absence of overt degeneration. Cell Death Dis. 10, 7 (2018).

    PubMed  PubMed Central  Google Scholar 

  37. Gorth, D. J., Shapiro, I. M. & Risbud, M. V. A new understanding of the role of IL-1 in age-related intervertebral disc degeneration in a murine model. J. Bone Miner. Res. 34, 1531–1542 (2019).

    CAS  PubMed  Google Scholar 

  38. Le Maitre, C. L., Freemont, A. J. & Hoyland, J. A. Human disc degeneration is associated with increased MMP 7 expression. Biotech. Histochem. 81, 125–131 (2006).

    PubMed  Google Scholar 

  39. Le Maitre, C. L., Freemont, A. J. & Hoyland, J. A. Localization of degradative enzymes and their inhibitors in the degenerate human intervertebral disc. J. Pathol. 204, 47–54 (2004).

    PubMed  Google Scholar 

  40. Buckwalter, J. A. Aging and degeneration of the human intervertebral disc. Spine 20, 1307–1314 (1995).

    CAS  PubMed  Google Scholar 

  41. Porchet, F. et al. Relationship between severity of lumbar disc disease and disability scores in sciatica patients. Neurosurgery 50, 1253–1260 (2002).

    PubMed  Google Scholar 

  42. Freemont, A. J. et al. Nerve ingrowth into diseased intervertebral disc in chronic back pain. Lancet 350, 178–181 (1997).

    CAS  PubMed  Google Scholar 

  43. Brown, M. F. et al. Sensory and sympathetic innervation of the vertebral endplate in patients with degenerative disc disease. J. Bone Joint Surg. Br. 79, 147–153 (1997).

    CAS  PubMed  Google Scholar 

  44. Bailey, J. F., Liebenberg, E., Degmetich, S. & Lotz, J. C. Innervation patterns of PGP 9.5-positive nerve fibers within the human lumbar vertebra. J. Anat. 218, 263–270 (2011).

    PubMed  PubMed Central  Google Scholar 

  45. Binch, A. L. et al. Nerves are more abundant than blood vessels in the degenerate human intervertebral disc. Arthritis Res. Ther. 17, 370 (2015).

    PubMed  PubMed Central  Google Scholar 

  46. Lama, P., Le Maitre, C. L., Harding, I. J., Dolan, P. & Adams, M. A. Nerves and blood vessels in degenerated intervertebral discs are confined to physically disrupted tissue. J. Anat. 233, 86–97 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Johnson, W. E., Caterson, B., Eisenstein, S. M. & Roberts, S. Human intervertebral disc aggrecan inhibits endothelial cell adhesion and cell migration in vitro. Spine 30, 1139–1147 (2005).

    PubMed  Google Scholar 

  48. Johnson, W. E. et al. Human intervertebral disc cells promote nerve growth over substrata of human intervertebral disc aggrecan. Spine 31, 1187–1193 (2006).

    PubMed  Google Scholar 

  49. Stefanakis, M. et al. Annulus fissures are mechanically and chemically conducive to the ingrowth of nerves and blood vessels. Spine 37, 1883–1891 (2012).

    PubMed  Google Scholar 

  50. Binch, A. L. A. et al. Expression and regulation of neurotrophic and angiogenic factors during human intervertebral disc degeneration. Arthritis Res. Ther. 16, 416 (2014).

    PubMed  Google Scholar 

  51. Krock, E. et al. Toll-like receptor 2 regulates nerve growth factor synthesis via NF-κB signaling in human intervertebral disc cells. Glob. Spine J. https://doi.org/10.1055/s-0036-1582634 (2017).

    Article  Google Scholar 

  52. Purmessur, D., Freemont, A. J. & Hoyland, J. A. Expression and regulation of neurotrophins in the nondegenerate and degenerate human intervertebral disc. Arthritis Res. Ther. 10, R99 (2008).

    PubMed  PubMed Central  Google Scholar 

  53. Lai, A. et al. Annular puncture with tumor necrosis factor-alpha injection enhances painful behavior with disc degeneration in vivo. Spine J. 16, 420–431 (2016).

    PubMed  Google Scholar 

  54. Richardson, S. M. et al. Degenerate human nucleus pulposus cells promote neurite outgrowth in neural cells. PLoS ONE 7, e47735 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Aoki, Y. et al. Disc inflammation potentially promotes axonal regeneration of dorsal root ganglion neurons innervating lumbar intervertebral disc in rats. Spine 29, 2621–2626 (2004).

    PubMed  Google Scholar 

  56. Kepler, C. K. et al. Substance P stimulates production of inflammatory cytokines in human disc cells. Spine 38, E1291–E1299 (2013).

    PubMed  Google Scholar 

  57. Miyagi, M. et al. ISSLS Prize winner: Increased innervation and sensory nervous system plasticity in a mouse model of low back pain due to intervertebral disc degeneration. Spine 39, 1345–1354 (2014).

    PubMed  Google Scholar 

  58. Krock, E. et al. Painful, degenerating intervertebral discs up-regulate neurite sprouting and CGRP through nociceptive factors. J. Cell. Mol. Med. 18, 1213–1225 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Koerner, J. D. et al. The effect of substance P on an intervertebral disc rat organ culture model. Spine 41, 1851–1859 (2016).

    PubMed  Google Scholar 

  60. Kepler, C. K. et al. Substance P receptor antagonist suppresses inflammatory cytokine expression in human disc cells. Spine 40, 1261–1269 (2015).

    PubMed  Google Scholar 

  61. Torre, O. M., Mroz, V., Bartelstein, M. K., Huang, A. H. & Iatridis, J. C. Annulus fibrosus cell phenotypes in homeostasis and injury: implications for regenerative strategies. Ann. NY Acad. Sci. 1442, 61–78 (2019).

    PubMed  Google Scholar 

  62. Cherkin, D. C., Wheeler, K. J., Barlow, W. & Deyo, R. A. Medication use for low back pain in primary care. Spine 23, 607–614 (1998).

    CAS  PubMed  Google Scholar 

  63. Malanga, G. A. & Nadler, S. F. Nonoperative treatment of low back pain. Mayo Clin. Proc. 74, 1135–1148 (1999).

    CAS  PubMed  Google Scholar 

  64. Cherkin, D. C., Deyo, R. A., Battie, M., Street, J. & Barlow, W. A comparison of physical therapy, chiropractic manipulation, and provision of an educational booklet for the treatment of patients with low back pain. N. Engl. J. Med. 339, 1021–1029 (1998).

    CAS  PubMed  Google Scholar 

  65. Mirza, S. K. & Deyo, R. A. Systematic review of randomized trials comparing lumbar fusion surgery to nonoperative care for treatment of chronic back pain. Spine 32, 816–823 (2007).

    PubMed  Google Scholar 

  66. Chou, R. & Huffman, L. H. Medications for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline. Ann. Intern. Med. 147, 505–514 (2007).

    PubMed  Google Scholar 

  67. Chou, R. et al. Interventional therapies, surgery, and interdisciplinary rehabilitation for low back pain: an evidence-based clinical practice guideline from the American Pain Society. Spine 34, 1066–-1077 (2009).

    PubMed  Google Scholar 

  68. Van Alphen, H. A. M., Braakman, R., Bezemer, P. D., Broere, G. & Berfelo, M. W. Chemonucleolysis versus discectomy: a randomized multicenter trial. J. Neurosurg. 70, 869–875 (1989).

    PubMed  Google Scholar 

  69. Matsuyama, Y., Chiba, K., Iwata, H., Seo, T. & Toyama, Y. A multicenter, randomized, double-blind, dose-finding study of condoliase in patients with lumbar disc herniation. J. Neurosurg. Spine 28, 499–511 (2018).

    PubMed  Google Scholar 

  70. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03704363 (2020).

  71. Genevay, S. et al. Adalimumab in acute sciatica reduces the long-term need for surgery: a 3-year follow-up of a randomised double-blind placebo-controlled trial. Ann. Rheum. Dis. 71, 560–562 (2012).

    CAS  PubMed  Google Scholar 

  72. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02528253 (2020).

  73. Zhu, J. et al. Sustained release of GDF5 from a designed coacervate attenuates disc degeneration in a rat model. Acta Biomater. 86, 300–311 (2019).

    CAS  PubMed  Google Scholar 

  74. Williams, F. M. et al. GDF5 single-nucleotide polymorphism rs143383 is associated with lumbar disc degeneration in Northern European women. Arthritis Rheum. 63, 708–712 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT01158924 (2016).

  76. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT00813813 (2016).

  77. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT01124006 (2016).

  78. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT01182337 (2016).

  79. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/study/NCT03263611 (2020).

  80. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT01526330 (2015).

  81. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/study/NCT02320019 (2016).

  82. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/study/NCT03246399 (2019).

  83. Sakai, D. et al. Exhaustion of nucleus pulposus progenitor cells with ageing and degeneration of the intervertebral disc. Nat. Commun. 3, 1264 (2012).

    PubMed  Google Scholar 

  84. Strassburg, S., Richardson, S. M., Freemont, A. J. & Hoyland, J. A. Co-culture induces mesenchymal stem cell differentiation and modulation of the degenerate human nucleus pulposus cell phenotype. Regen. Med. 5, 701–711 (2010).

    CAS  PubMed  Google Scholar 

  85. Svanvik, T. et al. Human disk cells from degenerated disks and mesenchymal stem cells in co-culture result in increased matrix production. Cells Tissues Organs 191, 2–11 (2010).

    CAS  PubMed  Google Scholar 

  86. Watanabe, T. et al. Human nucleus pulposus cells significantly enhanced biological properties in a coculture system with direct cell-to-cell contact with autologous mesenchymal stem cells. J. Orthop. Res. 28, 623–630 (2010).

    CAS  PubMed  Google Scholar 

  87. Vedicherla, S. & Buckley, C. T. Cell-based therapies for intervertebral disc and cartilage regeneration — Current concepts, parallels, and perspectives. J. Orthop. Res. 35, 8–22 (2017).

    PubMed  Google Scholar 

  88. Iatridis, J. C., Kang, J., Kandel, R. & Risbud, M. V. New horizons in spine research: intervertebral disc repair and regeneration. J. Orthop. Res. 35, 5–7 (2017).

    PubMed  PubMed Central  Google Scholar 

  89. Buckley, C. T. et al. Critical aspects and challenges for intervertebral disc repair and regeneration — Harnessing advances in tissue engineering. JOR Spine 1, e1029 (2018).

    PubMed  PubMed Central  Google Scholar 

  90. Sakai, D. & Andersson, G. B. J. Stem cell therapy for intervertebral disc regeneration: obstacles and solutions. Nat. Rev. Rheumatol. 11, 243 (2015).

    PubMed  Google Scholar 

  91. Risbud, M. V., Schaer, T. P. & Shapiro, I. M. Toward an understanding of the role of notochordal cells in the adult intervertebral disc: from discord to accord. Dev. Dyn. 239, 2141–2148 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. McCann, M. R., Tamplin, O. J., Rossant, J. & Seguin, C. A. Tracing notochord-derived cells using a Noto-cre mouse: implications for intervertebral disc development. Dis. Model. Mech. 5, 73–82 (2012).

    CAS  PubMed  Google Scholar 

  93. Thompson, K., Moore, S., Tang, S., Wiet, M. & Purmessur, D. The chondrodystrophic dog: a clinically relevant intermediate-sized animal model for the study of intervertebral disc-associated spinal pain. JOR Spine 1, e1011 (2018).

    PubMed  PubMed Central  Google Scholar 

  94. Thorpe, A. A. et al. Leaping the hurdles in developing regenerative treatments for the intervertebral disc from preclinical to clinical. JOR Spine 1, e1027 (2018).

    PubMed  PubMed Central  Google Scholar 

  95. Thorpe, A. A., Sammon, C. & Le Maitre, C. ‘Cell or Not to Cell’ that is the question: for intervertebral disc regeneration? J. Stem Cell Res. Dev. Ther. https://doi.org/10.24966/SRDT-2060/100003 (2015).

    Article  Google Scholar 

  96. Meisel, H. J. et al. Clinical experience in cell-based therapeutics: intervention and outcome. Eur. Spine J. 15, 397–405 (2006).

    PubMed Central  Google Scholar 

  97. Meisel, H. J. et al. Clinical experience in cell-based therapeutics: disc chondrocyte transplantation: A treatment for degenerated or damaged intervertebral disc. Biomol. Eng. 24, 5–21 (2007).

    CAS  PubMed  Google Scholar 

  98. Coric, D., Pettine, K., Sumich, A. & Boltes, M. O. Prospective study of disc repair with allogeneic chondrocytes presented at the 2012 Joint Spine Section Meeting. J. Neurosurg. Spine 18, 85–95 (2013).

    PubMed  Google Scholar 

  99. Mochida, J. et al. Intervertebral disc repair with activated nucleus pulposus cell transplantation: a three-year, prospective clinical study of its safety. Eur. Cell Mater. 29, 202–212 (2015).

    CAS  PubMed  Google Scholar 

  100. Tschugg, A. et al. A prospective randomized multicenter phase I/II clinical trial to evaluate safety and efficacy of NOVOCART disk plus autologous disk chondrocyte transplantation in the treatment of nucleotomized and degenerative lumbar disks to avoid secondary disease: safety results of Phase I–a short report. Neurosurg. Rev. 40, 155–162 (2017).

    PubMed  Google Scholar 

  101. Beall, D. P., Wilson, G. L., Bishop, R. & Tally, W. VAST clinical trial: safely supplementing tissue lost to degenerative disc disease. Int. J. Spine Surg. 14, 239–253 (2020).

    PubMed  PubMed Central  Google Scholar 

  102. Yoshikawa, T., Ueda, Y., Miyazaki, K., Koizumi, M. & Takakura, Y. Disc regeneration therapy using marrow mesenchymal cell transplantation: a report of two case studies. Spine 35, E475–E480 (2010).

    PubMed  Google Scholar 

  103. Orozco, L. et al. Intervertebral disc repair by autologous mesenchymal bone marrow cells: a pilot study. Transplantation 92, 822–828 (2011).

    PubMed  Google Scholar 

  104. Elabd, C. et al. Intra-discal injection of autologous, hypoxic cultured bone marrow-derived mesenchymal stem cells in five patients with chronic lower back pain: a long-term safety and feasibility study. J. Transl Med. 14, 253 (2016).

    PubMed  PubMed Central  Google Scholar 

  105. Noriega, D. C. et al. Intervertebral disc repair by allogeneic mesenchymal bone marrow cells: a randomized controlled trial. Transplantation 101, 1945–1951 (2017).

    PubMed  Google Scholar 

  106. Centeno, C. et al. Treatment of lumbar degenerative disc disease-associated radicular pain with culture-expanded autologous mesenchymal stem cells: a pilot study on safety and efficacy. J. Transl Med. 15, 197 (2017).

    PubMed  PubMed Central  Google Scholar 

  107. Blanco, J. F. et al. Autologous mesenchymal stromal cells embedded in tricalcium phosphate for posterolateral spinal fusion: results of a prospective phase I/II clinical trial with long-term follow-up. Stem Cell Res. Ther. 10, 63 (2019).

    PubMed  PubMed Central  Google Scholar 

  108. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03737461 (2020).

  109. European Medicines Agency. EU Clinical Trials Register https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-002092-25/ES (2020).

  110. Grunhagen, T., Wilde, G., Soukane, D. M., Shirazi-Adl, S. A. & Urban, J. P. Nutrient supply and intervertebral disc metabolism. J. Bone Joint Surg. Am. 88, 30–35 (2006).

    PubMed  Google Scholar 

  111. Pettine, K. A., Murphy, M. B., Suzuki, R. K. & Sand, T. T. Percutaneous injection of autologous bone marrow concentrate cells significantly reduces lumbar discogenic pain through 12 months. Stem Cell 33, 146–156 (2015).

    CAS  Google Scholar 

  112. 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. 15, 12 (2017).

    PubMed  Google Scholar 

  113. Kumar, H. et al. Safety and tolerability of intradiscal implantation of combined autologous adipose-derived mesenchymal stem cells and hyaluronic acid in patients with chronic discogenic low back pain: 1-year follow-up of a phase I study. Stem Cell Res. Ther. 8, 262 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Hohaus, C., Ganey, T. M., Minkus, Y. & Meisel, H. J. Cell transplantation in lumbar spine disc degeneration disease. Eur. Spine J. 17, 492–503 (2008).

    PubMed  PubMed Central  Google Scholar 

  115. Ganey, T., Hutton, W. C., Moseley, T., Hedrick, M. & Meisel, H. J. Intervertebral disc repair using adipose tissue-derived stem and regenerative cells: experiments in a canine model. Spine 34, 2297–2304 (2009).

    PubMed  Google Scholar 

  116. Hussain, I. et al. Mesenchymal stem cell-seeded high-density collagen gel for annular repair: 6-week results from in vivo sheep models. Neurosurgery 85, E350–E359 (2018).

    Google Scholar 

  117. Mesoblast Ltd. Chronic low back pain due to disc degeneration, https://www.mesoblast.com/product-candidates/spine-orthopedic-disorders/chronic-discogenic-low-back-pain (2020).

  118. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01290367 (2020).

  119. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02412735 (2020).

  120. Satué, M., Schüler, C., Ginner, N. & Erben, R. G. Intra-articularly injected mesenchymal stem cells promote cartilage regeneration, but do not permanently engraft in distant organs. Sci. Rep. 9, 10153 (2019).

    PubMed  PubMed Central  Google Scholar 

  121. Enomoto, T. et al. Timing of intra-articular injection of synovial mesenchymal stem cells affects cartilage restoration in a partial thickness cartilage defect model in rats. Cartilage 11, 122–129 (2020).

    PubMed  Google Scholar 

  122. Park, Y. B. et al. Single-stage cell-based cartilage repair in a rabbit model: cell tracking and in vivo chondrogenesis of human umbilical cord blood-derived mesenchymal stem cells and hyaluronic acid hydrogel composite. Osteoarthr. Cartil. 25, 570–580 (2017).

    CAS  Google Scholar 

  123. Lee, M. J. et al. Proteomic analysis of tumor necrosis factor-α-induced secretome of human adipose tissue-derived mesenchymal stem cells. J. Proteome Res. 9, 1754–1762 (2010).

    CAS  PubMed  Google Scholar 

  124. Peck, S. et al. Hypoxic preconditioning enhances bone marrow-derived mesenchymal stem cell survival in a low oxygen and nutrient-limited 3D microenvironment. Cartilage https://doi.org/10.1177/1947603519841675 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Yang, S., Wu, C., Shih, T., Sun, Y. & Lin, F. In vitro study on interaction between human nucleus pulposus cells and mesenchymal stem cells through paracrine stimulation. Spine 33, 1951–1957 (2008).

    PubMed  Google Scholar 

  126. Teixeira, G. Q. et al. Immunomodulation of human mesenchymal stem/stromal cells in intervertebral disc degeneration: insights from a proinflammatory/degenerative ex vivo model. Spine 43, E673–E682 (2018).

    PubMed  Google Scholar 

  127. Brisby, H. et al. 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 Cell Dev. 22, 804–814 (2013).

    CAS  Google Scholar 

  128. Lv, F. et al. The potential of umbilical cord derived mesenchymal stem cells in intervertebral disc repair. Glob. Spine J. 4 (Suppl. 1), s0034-1376649 (2017).

    Google Scholar 

  129. Galleu, A. et al. Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation. Sci. Transl Med. 9, eaam7828 (2017).

    PubMed  Google Scholar 

  130. de Witte, S. F. H. et al. Immunomodulation by therapeutic mesenchymal stromal cells (MSC) is triggered through phagocytosis of MSC by monocytic cells. Stem Cell 36, 602–615 (2018).

    Google Scholar 

  131. Bruno, S. et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J. Am. Soc. Nephrol. 20, 1053–1067 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Alvarez-Viejo, M. Mesenchymal stem cells from different sources and their derived exosomes: a pre-clinical perspective. World J. Stem Cell 12, 100–109 (2020).

    Google Scholar 

  133. Wiklander, O. P. B., Brennan, M. A., Lotvall, J., Breakefield, X. O. & El Andaloussi, S. Advances in therapeutic applications of extracellular vesicles. Sci. Transl Med. 11, eaav8521 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Cheng, X. et al. Mesenchymal stem cells deliver exogenous miR-21 via exosomes to inhibit nucleus pulposus cell apoptosis and reduce intervertebral disc degeneration. J. Cell Mol. Med. 22, 261–276 (2018).

    CAS  PubMed  Google Scholar 

  135. Shi, B. et al. Bone marrow mesenchymal stem cell-derived exosomal miR-21 protects C-kit+ cardiac stem cells from oxidative injury through the PTEN/PI3K/Akt axis. PLoS ONE 13, e0191616 (2018).

    PubMed  PubMed Central  Google Scholar 

  136. Fang, S. et al. Umbilical cord-derived mesenchymal stem cell-derived exosomal microRNAs suppress myofibroblast differentiation by inhibiting the transforming growth factor-β/SMAD2 pathway during wound healing. Stem Cell Transl Med. 5, 1425–1439 (2016).

    CAS  Google Scholar 

  137. Cui, G. H. et al. Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice. FASEB J. 32, 654–668 (2018).

    CAS  PubMed  Google Scholar 

  138. Xia, C. et al. Mesenchymal stem cell-derived exosomes ameliorate intervertebral disc degeneration via anti-oxidant and anti-inflammatory effects. Free Radic. Biol. Med. 143, 1–15 (2019).

    CAS  PubMed  Google Scholar 

  139. Liao, Z. et al. Exosomes from mesenchymal stem cells modulate endoplasmic reticulum stress to protect against nucleus pulposus cell death and ameliorate intervertebral disc degeneration in vivo. Theranostics 9, 4084–4100 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Pang, X., Yang, H. & Peng, B. Human umbilical cord mesenchymal stem cell transplantation for the treatment of chronic discogenic low back pain. Pain Physician 17, 525–530 (2014).

    Google Scholar 

  141. Vadala, G. et al. Coculture of bone marrow mesenchymal stem cells and nucleus pulposus cells modulate gene expression profile without cell fusion. Spine 33, 870–876 (2008).

    PubMed  Google Scholar 

  142. Richardson, S. M. et al. Intervertebral disc cell-mediated mesenchymal stem cell differentiation. Stem Cell 24, 707–716 (2006).

    CAS  Google Scholar 

  143. Cagliani, J., Grande, D., Molmenti, E. P., Miller, E. J. & Rilo, H. L. R. Immunomodulation by mesenchymal stromal cells and their clinical applications. J. Stem Cell Regen. Biol. https://doi.org/10.15436/2471-0598.17.022 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Okuma, M., Mochida, J., Nishimura, K., Sakabe, K. & Seiki, K. Reinsertion of stimulated nucleus pulposus cells retards intervertebral disc degeneration: an in vitro and in vivo experimental study. J. Orthop. Res. 18, 988–997 (2000).

    CAS  PubMed  Google Scholar 

  145. Yamamoto, Y. et al. Upregulation of the viability of nucleus pulposus cells by bone marrow-derived stromal cells: significance of direct cell-to-cell contact in coculture system. Spine 29, 1508–1514 (2004).

    PubMed  Google Scholar 

  146. Yamamoto, Y., Mochida, J., Sakai, D. & Nomura, T. Reinsertion of nucleus pulposus cells activated by mesenchymal stem cells using coculture method decelerated intervertebral disc degeneration [abstract 72]. Spine J. 3 (5 Suppl.), 101–102 (2003).

    Google Scholar 

  147. Wang, W. et al. Transplantation of hypoxic-preconditioned bone mesenchymal stem cells retards intervertebral disc degeneration via enhancing implanted cell survival and migration in rats. Stem Cells Int. 2018, 7564159 (2018).

    PubMed  PubMed Central  Google Scholar 

  148. Vadalà, G. et al. Mesenchymal stem cells injection in degenerated intervertebral disc: cell leakage may induce osteophyte formation. J. Tissue Eng. Regen. Med. 6, 348–355 (2012).

    PubMed  Google Scholar 

  149. Bertram, H. et al. Matrix-assisted cell transfer for intervertebral disc cell therapy. Biochem. Biophys. Res. Commun. 331, 1185–1192 (2005).

    CAS  PubMed  Google Scholar 

  150. Omlor, G. W. et al. 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 (2010).

    CAS  PubMed  Google Scholar 

  151. Nachemson, A. L. Disc pressure measurements. Spine 6, 93–97 (1981).

    CAS  PubMed  Google Scholar 

  152. Sakai, D. et al. Regenerative effects of transplanting mesenchymal stem cells embedded in atelocollagen to the degenerated intervertebral disc. Biomaterials 27, 335–345 (2006).

    CAS  PubMed  Google Scholar 

  153. Hu, J. et al. Functional compressive mechanics and tissue biocompatibility of an injectable SF/PU hydrogel for nucleus pulposus replacement. Sci. Rep. 7, 2347 (2017).

    PubMed  PubMed Central  Google Scholar 

  154. Steffen, F., Bertolo, A., Affentranger, R., Ferguson, S. J. & Stoyanov, J. Treatment of naturally degenerated canine lumbosacral intervertebral discs with autologous mesenchymal stromal cells and collagen microcarriers: a prospective clinical study. Cell Transplant. 28, 201–211 (2018).

    PubMed  PubMed Central  Google Scholar 

  155. Sun, Z., Liu, B. & Luo, Z. J. The immune privilege of the intervertebral disc: implications for intervertebral disc degeneration treatment. Int. J. Med. Sci. 17, 685–692 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Ryan, J. M., Barry, F. P., Murphy, J. M. & Mahon, B. P. Mesenchymal stem cells avoid allogeneic rejection. J. Inflamm. 2, 8 (2005).

    Google Scholar 

  157. Khan, A. N. et al. Inflammatory biomarkers of low back pain and disc degeneration: a review. Ann. NY Acad. Sci. 1410, 68–84 (2017).

    PubMed  Google Scholar 

  158. Rampersaud, Y. R., Bidos, A., Fanti, C. & Perruccio, A. V. The need for multidimensional stratification of chronic low back pain (LBP). Spine 42, E1318–E1325 (2017).

    PubMed  PubMed Central  Google Scholar 

  159. Roberts, S. et al. Matrix metalloproteinases and aggrecanase: their role in disorders of the human intervertebral disc. Spine 25, 3005–3013 (2000).

    CAS  PubMed  Google Scholar 

  160. Lama, P. et al. Physical disruption of intervertebral disc promotes cell clustering and a degenerative phenotype. Cell Death Discov. 5, 154 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Antoniou, J. et al. The human lumbar intervertebral disc: evidence for changes in the biosynthesis and denaturation of the extracellular matrix with growth, maturation, ageing, and degeneration. J. Clin. Invest. 98, 996–1003 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Binch, A. L. A., Richardson, S. M., Hoyland, J. A. & Barry, F. P. Combinatorial conditioning of adipose derived-mesenchymal stem cells enhances their neurovascular potential: implications for intervertebral disc degeneration. JOR Spine 2, e1072 (2019).

    PubMed  PubMed Central  Google Scholar 

  163. Cunningham, C. J., Redondo-Castro, E. & Allan, S. M. The therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke. J. Cereb. Blood Flow. Metab. 38, 1276–1292 (2018).

    PubMed  PubMed Central  Google Scholar 

  164. Bortolotti, F. et al. In vivo therapeutic potential of mesenchymal stromal cells depends on the source and the isolation procedure. Stem Cell Rep. 4, 332–339 (2015).

    CAS  Google Scholar 

  165. Kim, Y. J., Kim, H. K., Cho, H. H., Bae, Y. C. & Jung, J. S. Direct comparison of human mesenchymal stem cells derived from adipose tissues and bone marrow in mediating neovascularization in response to vascular ischemia. Cell. Physiol. Biochem. 20, 867–876 (2007).

    CAS  PubMed  Google Scholar 

  166. Moon, M. H. et al. Human adipose tissue-derived mesenchymal stem cells improve postnatal neovascularization in a mouse model of hindlimb ischemia. Cell. Physiol. Biochem. 2006, 279–290 (2006).

    Google Scholar 

  167. Bianco, P. & Robey, P. G. Skeletal stem cells. Development 142, 1023–1027 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Wu, P. et al. Non-viral gene delivery systems for tissue repair and regeneration. J. Transl Med. 16, 29 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Trusov, G. A. et al. Investigation of transport and unpacking mechanisms of polyplexes for transfection efficacy on different cell lines. Dokl. Biochem. Biophys. 437, 77–79 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Lin, C. Y. et al. Treatment of intervertebral disk disease by the administration of mRNA encoding a cartilage-anabolic transcription factor. Mol. Ther. Nucleic Acids 16, 162–171 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Krupkova, O. et al. The potential of CRISPR/Cas9 genome editing for the study and treatment of intervertebral disc pathologies. JOR Spine 1, e1003 (2018).

    PubMed  PubMed Central  Google Scholar 

  172. Mayer, J. E. et al. Genetic polymorphisms associated with intervertebral disc degeneration. Spine J. 13, 299–317 (2013).

    PubMed  PubMed Central  Google Scholar 

  173. Stover, J. D. et al. CRISPR epigenome editing of AKAP150 in DRG neurons abolishes degenerative IVD-induced neuronal activation. Mol. Ther. 25, 2014–2027 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Yao, R. et al. CRISPR-Cas9/Cas12a biotechnology and application in bacteria. Synth. Syst. Biotechnol. 3, 135–149 (2018).

    PubMed  PubMed Central  Google Scholar 

  175. Pickar-Oliver, A. & Gersbach, C. A. The next generation of CRISPR-Cas technologies and applications. Nat. Rev. Mol. Cell Biol. 20, 490–507 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Ji, M. L. et al. Preclinical development of a microRNA-based therapy for intervertebral disc degeneration. Nat. Commun. 9, 5051 (2018).

    PubMed  PubMed Central  Google Scholar 

  177. Zhao, Y. et al. Sequence-specific inhibition of microRNA via CRISPR/CRISPRi system. Sci. Rep. 4, 3943 (2014).

    PubMed  PubMed Central  Google Scholar 

  178. Tang, R. et al. Differentiation of human induced pluripotent stem cells into nucleus pulposus-like cells. Stem Cell Res. Ther. 9, 61 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Zhao, Q. et al. MSCs derived from iPSCs with a modified protocol are tumor-tropic but have much less potential to promote tumors than bone marrow MSCs. Proc. Natl Acad. Sci. USA 112, 530–535 (2015).

    CAS  PubMed  Google Scholar 

  180. Lu, K. et al. Exosomes as potential alternatives to stem cell therapy for intervertebral disc degeneration: in-vitro study on exosomes in interaction of nucleus pulposus cells and bone marrow mesenchymal stem cells. Stem Cell Res. Ther. 8, 108 (2017).

    PubMed  PubMed Central  Google Scholar 

  181. Zhang, Z. G., Buller, B. & Chopp, M. Exosomes – beyond stem cells for restorative therapy in stroke and neurological injury. Nat. Rev. Neurol. 15, 193–203 (2019).

    PubMed  Google Scholar 

  182. Cabral, J., Ryan, A. E., Griffin, M. D. & Ritter, T. Extracellular vesicles as modulators of wound healing. Adv. Drug Deliv. Rev. 129, 394–406 (2018).

    CAS  PubMed  Google Scholar 

  183. Dai, J. et al. Microfluidic disc-on-a-chip device for mouse intervertebral disc-pitching a next-generation research platform to study disc degeneration. ACS Biomater. Sci. Eng. 5, 2041–2051 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Richardson, S. M. et al. Notochordal and nucleus pulposus marker expression is maintained by sub-populations of adult human nucleus pulposus cells through aging and degeneration. Sci. Rep. 7, 1501 (2017).

    PubMed  PubMed Central  Google Scholar 

  185. Minogue, B. M., Richardson, S. M., Zeef, L. A., Freemont, A. J. & Hoyland, J. A. Characterization of the human nucleus pulposus cell phenotype and evaluation of novel marker gene expression to define adult stem cell differentiation. Arthritis Rheum. 62, 3695–3705 (2010).

    PubMed  Google Scholar 

  186. Gilson, A., Dreger, M. & Urban, J. P. Differential expression level of cytokeratin 8 in cells of the bovine nucleus pulposus complicates the search for specific intervertebral disc cell markers. Arthritis Res. Ther. 12, R24 (2010).

    PubMed  PubMed Central  Google Scholar 

  187. Thorpe, A. A., Binch, A. L., Creemers, L. B., Sammon, C. & Le Maitre, C. Nucleus pulposus phenotypic markers to determine stem cell differentiation: fact or fiction? Oncotarget 7, 2189–2200 (2016).

    PubMed  Google Scholar 

  188. Risbud, M. V. et al. Defining the phenotype of young healthy nucleus pulposus cells: recommendations of the Spine Research Interest Group at the 2014 annual ORS meeting. J. Orthop. Res. 33, 283–293 (2015).

    PubMed  PubMed Central  Google Scholar 

  189. Mwale, F., Roughley, P. & Antoniou, J. Distinction between the extracellular matrix of the nucleus pulposus and hyaline cartilage: a requisite for tissue engineering of intervertebral disc. Eur. Cell Mater. 8, 58–63 (2004).

    CAS  PubMed  Google Scholar 

  190. Dominici, M. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8, 315–317 (2006).

    CAS  PubMed  Google Scholar 

  191. Bourin, P. et al. Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy 15, 641–648 (2013).

    PubMed  PubMed Central  Google Scholar 

  192. Frazer, A., Bunning, R. A., Thavarajah, M., Seid, J. M. & Russell, R. G. Studies on type II collagen and aggrecan production in human articular chondrocytes in vitro and effects of transforming growth factor-β and interleukin-1β. Osteoarthr. Cartil. 2, 235–245 (1994).

    CAS  Google Scholar 

  193. Haufe, S. M. W. & Mork, A. R. Intradiscal injection of hematopoietic stem cells in an attempt to rejuvenate the intervertebral discs. Stem Cell Dev. 15, 136–137 (2006).

    Google Scholar 

  194. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02440074 (2015).

  195. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01860417 (2017).

  196. European Medicines Agency. EU Clinical Trials Register https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-003160-44/DK (2020).

  197. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02529566 (2017).

  198. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03692221 (2019).

  199. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03340818 (2020).

  200. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04559295 (2020).

  201. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03912454 (2019).

  202. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01643681 (2019).

  203. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02338271 (2015).

  204. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03461458 (2019).

  205. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT4414592 (2020).

  206. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04499105 (2020).

  207. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01640457 (2020).

  208. European Medicines Agency. EU Clinical Trials Register https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-023830-22/DE (2020).

  209. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03347708 (2020).

  210. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03955315 (2019).

  211. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01771471 (2017).

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Acknowledgements

A.L.A.B., J.C.F. and E.A.G. received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 732163, the Celtic Advanced Life Science Innovation Network, an Ireland–Wales programme part funded by the European Regional Development Fund through the Welsh Government (grant no. 80885), and the Whitaker International Foundation, respectively.

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  1. These authors contributed equally: Abbie L. A. Binch and Joan C. Fitzgerald

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  1. Regenerative Medicine Institute (REMEDI), National University of Ireland Galway, Galway, Ireland

    Abbie L. A. Binch, Joan C. Fitzgerald, Emily A. Growney & Frank Barry

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A.L.A.B., J.C.F. and E.A.G. researched data for the article. All authors wrote the article and reviewed or edited the manuscript before submission. F.B. and A.L.A.B. contributed substantially to discussions of content.

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F.B. declares that he is a shareholder and director of Orbsen Therapeutics Ltd. A.L.A.B., E.A.G. and J.C.F. declare no competing interests.

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Binch, A.L.A., Fitzgerald, J.C., Growney, E.A. et al. Cell-based strategies for IVD repair: clinical progress and translational obstacles. Nat Rev Rheumatol 17, 158–175 (2021). https://doi.org/10.1038/s41584-020-00568-w

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