Advances in the role of extracellular vesicles in intervertebral disc degeneration_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

ZHANG Helong , WEI Yifan , MA Cheng , LI Lingzhi , TAO Zhiwen ,  REN Yongxin

Department of Orthopedics, the First Affiliated Hospital of Nanjing Medical University, Nanjing Jiangsu, 210029, P. R. China;

Corresponding author：

REN Yongxin, Email: renyongxin@aliyun.com

Keywords：

Extracellular vesicles; intervertebral disc degeneration; nucleus pulposus; cartilage endplates; annulus fibrosus

DOI：

10.7507/1002-1892.202210060

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To review the mechanism of extracellular vesicles (EVs) in treating intervertebral disc degeneration (IVDD). Methods The literature about EVs was reviewed and the biological characteristics and mechanism of EVs in the treatment of IVDD were summarized. Results EVs are a kind of nano-sized vesicles with a double-layered lipid membrane structure secreted by many types of cells. EVs contain many bioactive molecules and participate in the exchange of information between cells, thus they play important roles in inflammation, oxidative stress, senescence, apoptosis, and autophagy. Moreover, EVs are found to slow down the process of IVDD by delaying the pathological progression of the nucleus pulposus, cartilage endplates, and annulus fibrosus. Conclusion EVs is expected to become a new strategy for the treatment of IVDD, but the specific mechanism remains to be further studied.

Citation： ZHANG Helong, WEI Yifan, MA Cheng, LI Lingzhi, TAO Zhiwen, REN Yongxin. Advances in the role of extracellular vesicles in intervertebral disc degeneration. Chinese Journal of Reparative and Reconstructive Surgery, 2023, 37(2): 208-214. doi: 10.7507/1002-1892.202210060 Copy

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2.	Chen BL, Guo JB, Zhang HW, et al. Surgical versus non-operative treatment for lumbar disc herniation: a systematic review and meta-analysis. Clin Rehabil, 2018, 32(2): 146-160.
3.	Wolf P. The nature and significance of platelet products in human plasma. Br J Haematol, 1967, 13(3): 269-288.
4.	Pan BT, Johnstone RM. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell, 1983, 33(3): 967-978.
5.	Théry C, Witwer KW, 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. doi: 10.1080/20013078.2018.1535750.
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7.	Oeyen E, Van Mol K, Baggerman G, et al. Ultrafiltration and size exclusion chromatography combined with asymmetrical-flow field-flow fractionation for the isolation and characterisation of extracellular vesicles from urine. J Extracell Vesicles, 2018, 7(1): 1490143. doi: 10.1080/20013078.2018.1490143.
8.	DiStefano TJ, Vaso K, Danias G, et al. Extracellular vesicles as an emerging treatment option for intervertebral disc degeneration: Therapeutic potential, translational pathways, and regulatory considerations. Adv Healthc Mater, 2022, 11(5): e2100596. doi: 10.1002/adhm.202100596.
9.	de Vries S, Doeselaar MV, Meij B, et al. Notochordal cell matrix as a therapeutic agent for intervertebral disc regeneration. Tissue Eng Part A, 2019, 25(11-12): 830-841.
10.	McAllister MJ, Chemaly M, Eakin AJ, et al. NLRP3 as a potentially novel biomarker for the management of osteoarthritis. Osteoarthritis Cartilage, 2018, 26(5): 612-619.
11.	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.
12.	Liao Z, Liu H, Ma L, et al. Engineering extracellular vesicles restore the impaired cellular uptake and attenuate intervertebral disc degeneration. ACS Nano, 2021, 15(9): 14709-14724.
13.	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. doi: 10.1186/s10020-021-00355-7.
14.	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.
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16.	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. doi: 10.1155/2022/2948090.
17.	Lu K, Li HY, 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. doi: 10.1186/s13287-017-0563-9.
18.	Feng C, Yang M, Lan M, et al. ROS: Crucial Intermediators in the pathogenesis of intervertebral disc degeneration. Oxid Med Cell Longev, 2017, 2017: 5601593. doi: 10.1155/2017/5601593.
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23.	张涛, 钱济先, 姬振伟, 等. 沉默p53和p21基因延缓髓核细胞衰老退变实验研究. 中国修复重建外科杂志, 2012, 26(7): 796-802.
24.	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. doi: 10.1155/2021/9955448.
25.	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. doi: 10.1186/s13287-021-02362-1.
26.	Liao Z, Li S, Lu S, et al. Metformin facilitates mesenchymal stem cell-derived extracellular nanovesicles release and optimizes therapeutic efficacy in intervertebral disc degeneration. Biomaterials, 2021, 274: 120850. doi: 10.1016/j.biomaterials.2021.120850.
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28.	Zhang XB, Hu YC, Cheng P, et al. Targeted therapy for intervertebral disc degeneration: inhibiting apoptosis is a promising treatment strategy. Int J Med Sci, 2021, 18(13): 2799-2813.
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30.	Sun Z, Tang X, Li Q, et al. Mesenchymal stem cell extracellular vesicles-derived microRNA-194-5p delays the development of intervertebral disc degeneration by targeting TRAF6. Regen Ther, 2022, 19: 88-96.
31.	Hu Y, Tao R, Wang L, et al. Exosomes derived from bone mesenchymal stem cells alleviate compression-induced nucleus pulposus cell apoptosis by inhibiting oxidative stress. Oxid Med Cell Longev, 2021, 2021: 2310025. doi: 10.1155/2021/2310025.
32.	Song J, Chen ZH, Zheng CJ, et al. Exosome-transported circRNA_0000253 competitively adsorbs microRNA-141-5p and increases IDD. Mol Ther Nucleic Acids, 2020, 21: 1087-1099.
33.	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.
34.	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. doi: 10.12659/MSM.922928.
35.	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.
36.	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. doi: 10.1155/2020/6697577.
37.	Latifkar A, Ling L, Hingorani A, et al. Loss of Sirtuin 1 alters the secretome of breast cancer cells by impairing lysosomal integrity. Dev Cell, 2019, 49(3): 393-408.
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39.	Hu SQ, Zhang QC, Meng QB, et al. Autophagy regulates exosome secretion in rat nucleus pulposus cells via the RhoC/ROCK2 pathway. Exp Cell Res, 2020, 395(2): 112239. doi: 10.1016/j.yexcr.2020.112239.
40.	Yuan W, Che W, Jiang YQ, et al. Establishment of intervertebral disc degeneration model induced by ischemic sub-endplate in rat tail. Spine J, 2015, 15(5): 1050-1059.
41.	Langrana NA, Kale SP, Edwards WT, et al. Measurement and analyses of the effects of adjacent end plate curvatures on vertebral stresses. Spine J, 2006, 6(3): 267-278.
42.	Han Y, Li X, Yan M, et al. Oxidative damage induces apoptosis and promotes calcification in disc cartilage endplate cell through ROS/MAPK/NF-κB pathway: Implications for disc degeneration. Biochem Biophys Res Commun, 2019, 516(3): 1026-1032.
43.	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.
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48.	Johnson WE, Caterson B, Eisenstein SM, et al. Human intervertebral disc aggrecan inhibits endothelial cell adhesion and cell migration in vitro. Spine (Phila Pa 1976), 2005, 30(10): 1139-1147.
49.	Stefanakis M, Al-Abbasi M, Harding I, et al. Annulus fissures are mechanically and chemically conducive to the ingrowth of nerves and blood vessels. Spine (Phila Pa 1976), 2012, 37(22): 1883-1891.
50.	Wiet MG, Piscioneri A, Khan SN, et al. Mast cell-intervertebral disc cell interactions regulate inflammation, catabolism and angiogenesis in Discogenic Back Pain. Sci Rep, 2017, 7(1): 12492. doi: 10.1038/s41598-017-12666-z.
51.	Sun Z, Zhao H, Liu B, et al. AF cell derived exosomes regulate endothelial cell migration and inflammation: Implications for vascularization in intervertebral disc degeneration. Life Sci, 2021, 265: 118778. doi: 10.1016/j.lfs.2020.118778.
52.	Sun Z, Liu B, Liu ZH, et al. Notochordal-cell-derived exosomes induced by compressive load inhibit angiogenesis via the miR-140-5p/Wnt/β-Catenin axis. Mol Ther Nucleic Acids, 2020, 22: 1092-1106.
53.	Li ZQ, Kong L, Liu C, et al. Human bone marrow mesenchymal stem cell-derived exosomes attenuate IL-1β-induced annulus fibrosus cell damage. Am J Med Sci, 2020, 360(6): 693-700.
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1. Zhao L, Manchikanti L, Kaye AD, et al. Treatment of discogenic low back pain: Current treatment strategies and future options-a literature review. Curr Pain Headache Rep, 2019, 23(11): 86. doi: 10.1007/s11916-019-0821-x.
2. Chen BL, Guo JB, Zhang HW, et al. Surgical versus non-operative treatment for lumbar disc herniation: a systematic review and meta-analysis. Clin Rehabil, 2018, 32(2): 146-160.
3. Wolf P. The nature and significance of platelet products in human plasma. Br J Haematol, 1967, 13(3): 269-288.
4. Pan BT, Johnstone RM. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell, 1983, 33(3): 967-978.
5. Théry C, Witwer KW, 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. doi: 10.1080/20013078.2018.1535750.
6. van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol, 2018, 19(4): 213-228.
7. Oeyen E, Van Mol K, Baggerman G, et al. Ultrafiltration and size exclusion chromatography combined with asymmetrical-flow field-flow fractionation for the isolation and characterisation of extracellular vesicles from urine. J Extracell Vesicles, 2018, 7(1): 1490143. doi: 10.1080/20013078.2018.1490143.
8. DiStefano TJ, Vaso K, Danias G, et al. Extracellular vesicles as an emerging treatment option for intervertebral disc degeneration: Therapeutic potential, translational pathways, and regulatory considerations. Adv Healthc Mater, 2022, 11(5): e2100596. doi: 10.1002/adhm.202100596.
9. de Vries S, Doeselaar MV, Meij B, et al. Notochordal cell matrix as a therapeutic agent for intervertebral disc regeneration. Tissue Eng Part A, 2019, 25(11-12): 830-841.
10. McAllister MJ, Chemaly M, Eakin AJ, et al. NLRP3 as a potentially novel biomarker for the management of osteoarthritis. Osteoarthritis Cartilage, 2018, 26(5): 612-619.
11. 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.
12. Liao Z, Liu H, Ma L, et al. Engineering extracellular vesicles restore the impaired cellular uptake and attenuate intervertebral disc degeneration. ACS Nano, 2021, 15(9): 14709-14724.
13. 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. doi: 10.1186/s10020-021-00355-7.
14. 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.
15. Yu XJ, Liu QK, 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. doi: 10.1155/2022/8983667.
16. 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. doi: 10.1155/2022/2948090.
17. Lu K, Li HY, 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. doi: 10.1186/s13287-017-0563-9.
18. Feng C, Yang M, Lan M, et al. ROS: Crucial Intermediators in the pathogenesis of intervertebral disc degeneration. Oxid Med Cell Longev, 2017, 2017: 5601593. doi: 10.1155/2017/5601593.
19. Han Y, Xu X, Tang C, et al. Reactive oxygen species promote tubular injury in diabetic nephropathy: The role of the mitochon-drial ros-txnip-nlrp3 biological axis. Redox Biol, 2018, 16: 32-46.
20. Xia C, Zeng Z, Fang B, et al. Mesenchymal stem cell-derived exosomes ameliorate intervertebral disc degeneration via anti-oxidant and anti-inflammatory effects. Free Radic Biol Med, 2019, 143: 1-15.
21. Zhou ZM, Bao JP, Peng X, et al. Small extracellular vesicles from hypoxic mesenchymal stem cells alleviate intervertebral disc degeneration by delivering miR-17-5p. Acta Biomater, 2022, 140: 641-658.
22. Lan WR, Pan S, Li HY, 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. doi: 10.1155/2019/8404168.
23. 张涛, 钱济先, 姬振伟, 等. 沉默p53和p21基因延缓髓核细胞衰老退变实验研究. 中国修复重建外科杂志, 2012, 26(7): 796-802.
24. 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. doi: 10.1155/2021/9955448.
25. 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. doi: 10.1186/s13287-021-02362-1.
26. Liao Z, Li S, Lu S, et al. Metformin facilitates mesenchymal stem cell-derived extracellular nanovesicles release and optimizes therapeutic efficacy in intervertebral disc degeneration. Biomaterials, 2021, 274: 120850. doi: 10.1016/j.biomaterials.2021.120850.
27. Chen CC, Chen J, Wang WL, et al. Inhibition of the P53/P21 pathway attenuates the effects of senescent nucleus pulposus cell-derived exosomes on the senescence of nucleus pulposus cells. Orthop Surg, 2021, 13(2): 583-591.
28. Zhang XB, Hu YC, Cheng P, et al. Targeted therapy for intervertebral disc degeneration: inhibiting apoptosis is a promising treatment strategy. Int J Med Sci, 2021, 18(13): 2799-2813.
29. Cheng X, Zhang G, Zhang L, 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, 2018, 22(1): 261-276.
30. Sun Z, Tang X, Li Q, et al. Mesenchymal stem cell extracellular vesicles-derived microRNA-194-5p delays the development of intervertebral disc degeneration by targeting TRAF6. Regen Ther, 2022, 19: 88-96.
31. Hu Y, Tao R, Wang L, et al. Exosomes derived from bone mesenchymal stem cells alleviate compression-induced nucleus pulposus cell apoptosis by inhibiting oxidative stress. Oxid Med Cell Longev, 2021, 2021: 2310025. doi: 10.1155/2021/2310025.
32. Song J, Chen ZH, Zheng CJ, et al. Exosome-transported circRNA_0000253 competitively adsorbs microRNA-141-5p and increases IDD. Mol Ther Nucleic Acids, 2020, 21: 1087-1099.
33. 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.
34. 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. doi: 10.12659/MSM.922928.
35. 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.
36. 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. doi: 10.1155/2020/6697577.
37. Latifkar A, Ling L, Hingorani A, et al. Loss of Sirtuin 1 alters the secretome of breast cancer cells by impairing lysosomal integrity. Dev Cell, 2019, 49(3): 393-408.
38. Zhang QC, Hu SQ, Hu AN, 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.
39. Hu SQ, Zhang QC, Meng QB, et al. Autophagy regulates exosome secretion in rat nucleus pulposus cells via the RhoC/ROCK2 pathway. Exp Cell Res, 2020, 395(2): 112239. doi: 10.1016/j.yexcr.2020.112239.
40. Yuan W, Che W, Jiang YQ, et al. Establishment of intervertebral disc degeneration model induced by ischemic sub-endplate in rat tail. Spine J, 2015, 15(5): 1050-1059.
41. Langrana NA, Kale SP, Edwards WT, et al. Measurement and analyses of the effects of adjacent end plate curvatures on vertebral stresses. Spine J, 2006, 6(3): 267-278.
42. Han Y, Li X, Yan M, et al. Oxidative damage induces apoptosis and promotes calcification in disc cartilage endplate cell through ROS/MAPK/NF-κB pathway: Implications for disc degeneration. Biochem Biophys Res Commun, 2019, 516(3): 1026-1032.
43. 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.
44. Yuan FL, Xu RS, Ye JX, et al. Apoptotic bodies from endplate chondrocytes enhance the oxidative stress-induced mineralization by regulating PPi metabolism. J Cell Mol Med, 2019, 23(5): 3665-3675.
45. 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.
46. 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. doi: 10.3389/fcell.2021.648201.
47. Chen D, Jiang X. Exosomes-derived miR-125-5p from cartilage endplate stem cells regulates autophagy and ECM metabolism in nucleus pulposus by targeting SUV38H1. Exp Cell Res, 2022, 414(1): 113066. doi: 10.1016/j.yexcr.2022.113066.
48. Johnson WE, Caterson B, Eisenstein SM, et al. Human intervertebral disc aggrecan inhibits endothelial cell adhesion and cell migration in vitro. Spine (Phila Pa 1976), 2005, 30(10): 1139-1147.
49. Stefanakis M, Al-Abbasi M, Harding I, et al. Annulus fissures are mechanically and chemically conducive to the ingrowth of nerves and blood vessels. Spine (Phila Pa 1976), 2012, 37(22): 1883-1891.
50. Wiet MG, Piscioneri A, Khan SN, et al. Mast cell-intervertebral disc cell interactions regulate inflammation, catabolism and angiogenesis in Discogenic Back Pain. Sci Rep, 2017, 7(1): 12492. doi: 10.1038/s41598-017-12666-z.
51. Sun Z, Zhao H, Liu B, et al. AF cell derived exosomes regulate endothelial cell migration and inflammation: Implications for vascularization in intervertebral disc degeneration. Life Sci, 2021, 265: 118778. doi: 10.1016/j.lfs.2020.118778.
52. Sun Z, Liu B, Liu ZH, et al. Notochordal-cell-derived exosomes induced by compressive load inhibit angiogenesis via the miR-140-5p/Wnt/β-Catenin axis. Mol Ther Nucleic Acids, 2020, 22: 1092-1106.
53. Li ZQ, Kong L, Liu C, et al. Human bone marrow mesenchymal stem cell-derived exosomes attenuate IL-1β-induced annulus fibrosus cell damage. Am J Med Sci, 2020, 360(6): 693-700.
54. Elsharkasy OM, Nordin JZ, Hagey DW, et al. Extracellular vesicles as drug delivery systems: Why and how? Adv Drug Deliv Rev, 2020, 159: 332-343.
55. Meng W, He C, Hao Y, et al. Prospects and challenges of extracellular vesicle-based drug delivery system: considering cell source. Drug Deliv, 2020, 27(1): 585-598.
56. 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.
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