Mechanism of extracellular vesicles in the repair of intervertebral disc degeneration_Journal of Biomedical Engineering

Authors：

ZHU Shengxu ,  LI Zhonghai , 李忠海 , 审校

Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P. R. China;

Corresponding author：

LI Zhonghai, Email: lizhonghaispine@126.com

Keywords：

Extracellular vesicles; Intervertebral disc degeneration; Mechanism; Intervertebral disc repair; Signaling pathway

DOI：

10.7507/1001-5515.202403046

Video：

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Abstract Full text Figures/Tables Video References Cited by

Extracellular vesicles (EVs), defined as cell-secreted nanoscale vesicles that carry bioactive molecules, have emerged as a promising therapeutic strategy in tumor and tissue regeneration. Their potential in repairing intervertebral disc degeneration (IDD) through multidimensional regulatory mechanisms is a rapidly advancing field of research. This paper provided an overview of the mechanisms of EVs in IDD repair, thoroughly reviewed recent literature on EVs for IDD, domestically and internationally, and summarized their therapeutic mechanisms. In IDD repair, EVs could act through different mechanisms at the molecular, cellular, and tissue levels. At the molecular level, EVs could treat IDD by inhibiting inflammatory reactions, suppressing oxidative stress, and regulating the synthesis and decomposition of extracellular matrix. At the cellular level, EVs could treat IDD by inhibiting cellular pyroptosis, ferroptosis, and apoptosis and promoting cell proliferation and differentiation. At the tissue level, EVs could treat IDD by inhibiting neovascularization. EVs have a strong potential for clinical application in the treatment of IDD and deserve more profound study.

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11.	Zhu S, Wang J, Suo M, et al. Can extracellular vesicles be considered as a potential frontier in the treatment of intervertebral disc disease?. Ageing Res Rev, 2023, 92: 102094.
12.	Kumar H, Ha D H, Lee E J, 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, 2017, 8(1): 262.
13.	Oehme D, Goldschlager T, Ghosh P, et al. Cell-based therapies used to treat lumbar degenerative disc disease: a systematic review of animal studies and human clinical trials. Stem Cells Int, 2015, 2015: 946031.
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15.	Trakarnsanga K, Tipgomut C, Metheetrairut C, et al. Generation of an immortalised erythroid cell line from haematopoietic stem cells of a haemoglobin E/β-thalassemia patient. Sci Rep, 2020, 10(1): 16798.
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50.	Liao Z, Luo R, Li G, 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, 2019, 9(14): 4084-4100.
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52.	Song J, Chen Z H, Zheng C J, et al. Exosome-transported circRNA_0000253 competitively adsorbs microRNA-141-5p and increases IDD. Mol Ther Nucleic Acids, 2020, 21: 1087-1099.
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1. Hartvigsen J, Hancock M J, Kongsted A, et al. What low back pain is and why we need to pay attention. Lancet, 2018, 391(10137): 2356-2367.
2. 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, 2021, 17(3): 158-175.
3. Patil P, Niedernhofer L J, Robbins P D, et al. Cellular senescence in intervertebral disc aging and degeneration. Curr Mol Biol Rep, 2018, 4(4): 180-190.
4. Ruan D, He Q, Ding Y, et al. Intervertebral disc transplantation in the treatment of degenerative spine disease: a preliminary study. Lancet, 2007, 369(9566): 993-999.
5. Han I, Ropper A E, Konya D, et al. Biological approaches to treating intervertebral disk degeneration: devising stem cell therapies. Cell Transplant, 2015, 24(11): 2197-2208.
6. Sakai D, Grad S. Advancing the cellular and molecular therapy for intervertebral disc disease. Adv Drug Deliv Rev, 2015, 84: 159-171.
7. Hajiesmailpoor A, Mohamadi O, Farzanegan G, et al. Overview of stem cell therapy in intervertebral disc disease: clinical perspective. Curr Stem Cell Res Ther, 2023, 18(5): 595-607.
8. Larson J W, 3rd, Levicoff E A, Gilbertson L G, et al. Biologic modification of animal models of intervertebral disc degeneration. J Bone Joint Surg Am Vol, 2006, 88(Suppl 2): 83-87.
9. Moriguchi Y, Alimi M, Khair T, et al. Biological treatment approaches for degenerative disk disease: a literature review of in vivo animal and clinical data. Glob Spine J, 2016, 6(5): 497-518.
10. Sampara P, Banala R R, Vemuri S K, et al. Understanding the molecular biology of intervertebral disc degeneration and potential gene therapy strategies for regeneration: a review. Gene Ther, 2018, 25(2): 67-82.
11. Zhu S, Wang J, Suo M, et al. Can extracellular vesicles be considered as a potential frontier in the treatment of intervertebral disc disease?. Ageing Res Rev, 2023, 92: 102094.
12. Kumar H, Ha D H, Lee E J, 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, 2017, 8(1): 262.
13. Oehme D, Goldschlager T, Ghosh P, et al. Cell-based therapies used to treat lumbar degenerative disc disease: a systematic review of animal studies and human clinical trials. Stem Cells Int, 2015, 2015: 946031.
14. Yoon Y J, Kim O Y, Gho Y S. Extracellular vesicles as emerging intercellular communicasomes. BMB Rep, 2014, 47(10): 531-539.
15. Trakarnsanga K, Tipgomut C, Metheetrairut C, et al. Generation of an immortalised erythroid cell line from haematopoietic stem cells of a haemoglobin E/β-thalassemia patient. Sci Rep, 2020, 10(1): 16798.
16. Li M, Li R, Yang S, et al. Exosomes derived from bone marrow mesenchymal stem cells prevent acidic pH-induced damage in human nucleus pulposus cells. Med Sci Monit, 2020, 26: e922928.
17. Tong B, Liao Z, Liu H, et al. Augmenting intracellular cargo delivery of extracellular vesicles in hypoxic tissues through inhibiting hypoxia-induced endocytic recycling. ACS Nano, 2023, 17(3): 2537-2553.
18. Pan B T, Johnstone R M. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell, 1983, 33(3): 967-978.
19. Valadi H, Ekström K, Bossios A, et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol, 2007, 9(6): 654-659.
20. Kalluri R, Lebleu V S. The biology, function, and biomedical applications of exosomes. Science, 2020, 367(6478): eaau6977.
21. Yuana Y, Sturk A, Nieuwland R. Extracellular vesicles in physiological and pathological conditions. Blood Rev, 2013, 27(1): 31-39.
22. Liu D, Kou X, Chen C, et al. Circulating apoptotic bodies maintain mesenchymal stem cell homeostasis and ameliorate osteopenia via transferring multiple cellular factors. Cell Res, 2018, 28(9): 918-933.
23. Royo F, Théry C, Falcón-Pérez J M, et al. Methods for separation and characterization of extracellular vesicles: results of a worldwide survey performed by the ISEV rigor and standardization subcommittee. Cells, 2020, 9(9): 1955.
24. Lin S, Yu Z, Chen D, et al. Progress in microfluidics-based exosome separation and detection technologies for diagnostic applications. Small, 2020, 16(9): e1903916.
25. Ford T, Graham J, Rickwood D. Iodixanol: a nonionic iso-osmotic centrifugation medium for the formation of self-generated gradients. Anal Biochem, 1994, 220(2): 360-366.
26. Théry C, Witwer K W, Aikawa E, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles, 2018, 7(1): 1535750.
27. Xing H, Zhang Z, Mao Q, et al. Injectable exosome-functionalized extracellular matrix hydrogel for metabolism balance and pyroptosis regulation in intervertebral disc degeneration. J Nanobiotechnol, 2021, 19(1): 264.
28. Yuan X, Li T, Shi L, et al. Human umbilical cord mesenchymal stem cells deliver exogenous miR-26a-5p via exosomes to inhibit nucleus pulposus cell pyroptosis through METTL14/NLRP3. Mol Med, 2021, 27(1): 91.
29. Tilotta V, Vadalà G, Ambrosio L, et al. Mesenchymal stem cell-derived secretome enhances nucleus pulposus cell metabolism and modulates extracellular matrix gene expression in vitro. Front Bioeng Biotechnol, 2023, 11: 1152207.
30. Song Y, Li S, Geng W, et al. Sirtuin 3-dependent mitochondrial redox homeostasis protects against AGEs-induced intervertebral disc degeneration. Redox Biol, 2018, 19: 339-353.
31. Dai Z, Xia C, Zhao T, et al. Platelet-derived extracellular vesicles ameliorate intervertebral disc degeneration by alleviating mitochondrial dysfunction. Mater Today Bio, 2023, 18: 100512.
32. Xu J, Xie G, Yang W, et al. Platelet-rich plasma attenuates intervertebral disc degeneration via delivering miR-141-3p-containing exosomes. Cell Cycle, 2021, 20(15): 1487-1499.
33. Zhang Q C, Hu S Q, Hu A-N, et al. Autophagy-activated nucleus pulposus cells deliver exosomal miR-27a to prevent extracellular matrix degradation by targeting MMP-13. J Orthop Res, 2021, 39(9): 1921-1932.
34. Wang H, Li F, Ban W, et al. Human bone marrow mesenchymal stromal cell-derived extracellular vesicles promote proliferation of degenerated nucleus pulposus cells and the synthesis of extracellular matrix through the SOX4/Wnt/β-catenin axis. Front Physiol, 2021, 12: 723220.
35. Feng X, Li Y, Su Q, et al. Degenerative nucleus pulposus cells derived exosomes promoted cartilage endplate cells apoptosis and aggravated intervertebral disc degeneration. Front Mol Biosci, 2022, 9: 835976.
36. Zhuang Y, Song S, Xiao D, et al. Exosomes secreted by nucleus pulposus stem cells derived from degenerative intervertebral disc exacerbate annulus fibrosus cell degradation via let-7b-5p. Front Mol Biosci, 2021, 8: 766115.
37. Van Opdenbosch N, Lamkanfi M. Caspases in cell death, inflammation, and disease. Immunity, 2019, 50(6): 1352-1364.
38. Zhang J, Zhang J, Zhang Y, et al. Mesenchymal stem cells-derived exosomes ameliorate intervertebral disc degeneration through inhibiting pyroptosis. J Cell Mol Med, 2020, 24(20): 11742-11754.
39. Zhang X, Huang Z, Xie Z, et al. Homocysteine induces oxidative stress and ferroptosis of nucleus pulposus via enhancing methylation of GPX4. Free Radic Biol Med, 2020, 160: 552-565.
40. Yu X, Xu H, Liu Q, et al. Circ_0072464 shuttled by bone mesenchymal stem cell-secreted extracellular vesicles inhibits nucleus pulposus cell ferroptosis to relieve intervertebral disc degeneration. Oxid Med Cell Longev, 2022, 2022: 2948090.
41. Luo L, Jian X, Sun H, et al. Cartilage endplate stem cells inhibit intervertebral disc degeneration by releasing exosomes to nucleus pulposus cells to activate Akt/autophagy. Stem Cells, 2021, 39(4): 467-481.
42. Yu X J, Liu Q K, Lu R, et al. Bone marrow mesenchymal stem cell-derived extracellular vesicles carrying circ_0050205 attenuate intervertebral disc degeneration. Oxid Med Cell Longev, 2022, 2022: 8983667.
43. Cui S, Zhang L. MicroRNA-129-5p shuttled by mesenchymal stem cell-derived extracellular vesicles alleviates intervertebral disc degeneration via blockade of LRG1-mediated p38 MAPK activation. J Tissue Eng, 2021, 12: 20417314211021679.
44. Xie L, Chen Z, Liu M, et al. MSC-derived exosomes protect vertebral endplate chondrocytes against apoptosis and calcification via the miR-31-5p/ATF6 axis. Mol Ther Nucleic Acids, 2020, 22: 601-614.
45. Wen T, Wang H, Li Y, et al. Bone mesenchymal stem cell-derived extracellular vesicles promote the repair of intervertebral disc degeneration by transferring microRNA-199a. Cell Cycle, 2021, 20(3): 256-270.
46. Mariño G, Niso Santano M, Baehrecke E H, et al. Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol, 2014, 15(2): 81-94.
47. Luo L, Gong J, Wang Z, et al. Injectable cartilage matrix hydrogel loaded with cartilage endplate stem cells engineered to release exosomes for non-invasive treatment of intervertebral disc degeneration. Bioact Mater, 2022, 15: 29-43.
48. Xiao Q, Zhao Z, Teng Y, et al. BMSC-derived exosomes alleviate intervertebral disc degeneration by modulating AKT/mTOR-mediated autophagy of nucleus pulposus cells. Stem Cells Int, 2022, 2022: 9896444.
49. Zhu L, Shi Y, Liu L, et al. Mesenchymal stem cells-derived exosomes ameliorate nucleus pulposus cells apoptosis via delivering miR-142-3p: therapeutic potential for intervertebral disc degenerative diseases. Cell Cycle, 2020, 19(14): 1727-1739.
50. Liao Z, Luo R, Li G, 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, 2019, 9(14): 4084-4100.
51. Xiang H, Su W, Wu X, et al. Exosomes derived from human urine-derived stem cells inhibit intervertebral disc degeneration by ameliorating endoplasmic reticulum stress. Oxid Med Cell Longev, 2020, 2020: 6697577.
52. Song J, Chen Z H, Zheng C J, et al. Exosome-transported circRNA_0000253 competitively adsorbs microRNA-141-5p and increases IDD. Mol Ther Nucleic Acids, 2020, 21: 1087-1099.
53. Sun Y, Zhang W, Li X. Induced pluripotent stem cell-derived mesenchymal stem cells deliver exogenous miR-105-5p via small extracellular vesicles to rejuvenate senescent nucleus pulposus cells and attenuate intervertebral disc degeneration. Stem Cell Res Ther, 2021, 12(1): 286.
54. Lu K, Li H Y, Yang 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, 2017, 8(1): 108.
55. Guan M, Liu C, Zheng Q, et al. Exosome-laden injectable self-healing hydrogel based on quaternized chitosan and oxidized starch attenuates disc degeneration by suppressing nucleus pulposus senescence. Int J Biol Macromol, 2023, 232: 123479.
56. Sun Y, Li X, Yang X, et al. Small extracellular vesicles derived from adipocytes attenuate intervertebral disc degeneration in rats by rejuvenating senescent nucleus pulposus cells and endplate cells by delivering exogenous NAMPT. Oxid Med Cell Longev, 2021, 2021: 9955448.
57. Guo Z, Su W, Zhou R, et al. Exosomal MATN3 of urine-derived stem cells ameliorates intervertebral disc degeneration by antisenescence effects and promotes NPC proliferation and ECM synthesis by activating TGF-β. Oxid Med Cell Longev, 2021, 2021: 5542241.
58. Liao Z, Ke W, Liu H, et al. Vasorin-containing small extracellular vesicles retard intervertebral disc degeneration utilizing an injectable thermoresponsive delivery system. J Nanobiotechnol, 2022, 20(1): 420.
59. Wang B, Xu N, Cao L, et al. MiR-31 from mesenchymal stem cell-derived extracellular vesicles alleviates intervertebral disc degeneration by inhibiting NFAT5 and upregulating the Wnt/β-catenin pathway. Stem Cells Int, 2022, 2022: 2164057.
60. Hingert D, Ekström K, Aldridge J, et al. Extracellular vesicles from human mesenchymal stem cells expedite chondrogenesis in 3D human degenerative disc cell cultures. Stem Cell Res Ther, 2020, 11(1): 323.
61. Lan W R, Pan S, Li H Y, et al. Inhibition of the notch1 pathway promotes the effects of nucleus pulposus cell-derived exosomes on the differentiation of mesenchymal stem cells into nucleus pulposus-like cells in rats. Stem Cells Int, 2019, 2019: 8404168.
62. Luo L, Gong J, Zhang H, et al. Cartilage endplate stem cells transdifferentiate into nucleus pulposus cells via autocrine exosomes. Front Cell Dev Biol, 2021, 9: 648201.
63. Moon H J, Yurube T, Lozito T P, et al. Effects of secreted factors in culture medium of annulus fibrosus cells on microvascular endothelial cells: elucidating the possible pathomechanisms of matrix degradation and nerve in-growth in disc degeneration. Osteoarthr Cartil, 2014, 22(2): 344-354.
64. David G, Ciurea A V, Iencean S M, et al. Angiogenesis in the degeneration of the lumbar intervertebral disc. J Med Life, 2010, 3(2): 154-161.
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