Intervertebral disc degeneration (IVDD) is a major cause of low back pain, and several studies have evaluated the efficacy of extracellular vesicles (EVs) in the treatment of IVDD. The databases PubMed, Embase, and Cochrane Library were systematically searched from inception to the end of 2022 to identify studies investigating the therapeutic potential of cell-derived EVs for IVDD treatment. The following outcome measures were utilized: magnetic resonance imaging (MRI) Pfirrmann grading system, disc height index (DHI), histological grading, and apoptosis rate. A comprehensive meta-analysis was conducted, including a total of 13 articles comprising 19 studies involving 218 experimental animals. Comparative analysis between normal cell-derived EVs and placebo revealed significant reductions in MRI grade, increased DHI values, decreased nucleus pulposus cell apoptosis rates, and improved tissue grades. These findings collectively demonstrate the effective inhibition of IVDD through the application of EVs derived from cells. In conclusion, this study provides an updated synthesis of evidence supporting the efficacy of EVs as a promising therapeutic approach for IVDD treatment.
Get full access to this article
View all access options for this article.
References
1.
VergroesenPP, KingmaI, EmanuelKS, et al.Mechanics and biology in intervertebral disc degeneration: A vicious circle. Osteoarthritis Cartilage, 2015; 23(7):1057–1070; doi: 10.1016/j.joca.2015.03.028.
2.
RisbudMV, ShapiroIM. Role of cytokines in intervertebral disc degeneration: Pain and disc content. Nat Rev Rheumatol, 2014; 10(1):44–56; doi: 10.1038/nrrheum.2013.160.
3.
WuPH, KimHS, JangIT. Intervertebral Disc Diseases PART 2: A review of the current diagnostic and treatment strategies for intervertebral disc disease. Int J Mol Sci, 2020; 21(6):2135; doi: 10.3390/ijms21062135.
4.
ZhangW, SunT, LiY, et al.Application of stem cells in the repair of intervertebral disc degeneration. Stem Cell Res Ther, 2022; 13(1):70; doi: 10.1186/s13287-022-02745-y.
5.
GrangeatAM, ErarioMLA. The use of medical ozone in chronic intervertebral disc degeneration can be an etiological and conservative treatment. Int J Mol Sci, 2023; 24(7):6538; doi: 10.3390/ijms24076538.
6.
SilwalP, Nguyen-ThaiAM, MohammadHA, et al.Cellular senescence in intervertebral disc aging and degeneration: Molecular mechanisms and potential therapeutic opportunities. Biomolecules, 2023; 13(4):686; doi: 10.3390/biom13040686.
7.
SamparaP, BanalaRR, VemuriSK, 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; doi: 10.1038/s41434-018-0004-0.
8.
WilliamsFM, SambrookPN. Neck and back pain and intervertebral disc degeneration: Role of occupational factors. Best Pract Res Clin Rheumatol, 2011; 25(1):69–79; doi: 10.1016/j.berh.2011.01.007.
9.
CostăchescuB, NiculescuAG, TeleanuRI, et al.Recent advances in managing spinal intervertebral discs degeneration. Int J Mol Sci, 2022; 23(12):6460; doi: 10.3390/ijms23126460.
10.
GuptaD, ZicklerAM, El AndaloussiS. Dosing extracellular vesicles. Adv Drug Deliv Rev, 2021; 178:113961; doi: 10.1016/j.addr.2021.113961.
11.
van NielG, D'AngeloG, RaposoG. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol, 2018; 19(4):213–228; doi: 10.1038/nrm.2017.125.
12.
XingH, ZhangZ, MaoQ, et al.Injectable exosome-functionalized extracellular matrix hydrogel for metabolism balance and pyroptosis regulation in intervertebral disc degeneration. J Nanobiotechnol, 2021; 19(1):264; doi: 10.1186/s12951-021-00991-5.
13.
LiaoZ, LuoR, LiG, 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; doi: 10.7150/thno.33638.
14.
KrutZ, PelledG, GazitD, GazitZ. Stem cells and exosomes: New therapies for intervertebral disc degeneration. Cells, 2021; 10(9):2241; doi: 10.3390/cells10092241.
15.
WangH, LinS, YuH. Exosome-mediated repair of intervertebral disc degeneration: The potential role of miRNAs. Curr Stem Cell Res Ther, 2023; 5(4):1–11; doi: 10.2174/1574888X18666230504094233.
16.
PageMJ, McKenzieJE, BossuytPM, et al.The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ, 2021; 372:n71; doi: 10.1136/bmj.n71.
17.
GriffithJF, WangYX, AntonioGE, et al.Modified Pfirrmann grading system for lumbar intervertebral disc degeneration. Spine (Phila Pa 1976), 2007; 32(24):E708–E712; doi: 10.1097/BRS.0b013e31815a59a0.
18.
XieL, ChenZ, LiuM, 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; doi: 10.1016/j.omtn.2020.09.026.
19.
XiaC, ZengZ, FangB, 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; doi: 10.1016/j.freeradbiomed.2019.07.026.
20.
XiaoQ, ZhaoZ, TengY, 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; doi: 10.1155/2022/9896444.
21.
YuanQ, WangX, LiuL, et al.Exosomes derived from human placental mesenchymal stromal cells carrying AntagomiR-4450 alleviate intervertebral disc degeneration through upregulation of ZNF121. Stem Cells Dev, 2020; 29(16):1038–1058; doi: 10.1089/scd.2020.0083.
ChengX, ZhangG, ZhangL, 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; doi: 10.1111/jcmm.13316.
24.
SunY, ZhangW, LiX. 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.
25.
CuiS, ZhangL. 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; doi: 10.1177/20417314211021679.
26.
WangB, XuN, CaoL, 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; doi: 10.1155/2022/2164057.
27.
ZhouZM, BaoJP, PengX, 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; doi: 10.1016/j.actbio.2021.11.044.
28.
LiW, XuY, ChenW. Bone mesenchymal stem cells deliver exogenous lncRNA CAHM via exosomes to regulate macrophage polarization and ameliorate intervertebral disc degeneration. Exp Cell Res, 2022; 421(2):113408; doi: 10.1016/j.yexcr.2022.113408.
29.
FranciscoV, PinoJ, González-GayMÁ, et al.A new immunometabolic perspective of intervertebral disc degeneration. Nat Rev Rheumatol, 2022; 18(1):47–60; doi: 10.1038/s41584-021-00713-z.
30.
KirnazS, CapadonaC, WongT, et al.Fundamentals of intervertebral disc degeneration. World Neurosurg, 2022; 157:264–273; doi: 10.1016/j.wneu.2021.09.066.
31.
XinJ, WangY, ZhengZ, et al.Treatment of intervertebral disc degeneration. Orthop Surg, 2022; 14(7):1271–1280; doi: 10.1111/os.13254.
32.
VincentKF, BundockJ, DonaCPG, et al.Loss of lumbar disc height with age and its impact on pain and sensitivity associated behaviors in mice. Eur Spine J, 2023; 32(3):848–858; doi: 10.1007/s00586-023-07545-3.
33.
SidhomK, ObiPO, SaleemA. A review of exosomal isolation methods: Is size exclusion chromatography the best option?. Int J Mol Sci, 2020; 21(18):6466; doi: 10.3390/ijms21186466.
34.
LiL, HeJ, ZhangG, et al.Role of caspase family in intervertebral disc degeneration and its therapeutic prospects. Biomolecules, 2022; 12(8):1074; doi: 10.3390/biom12081074.
35.
ZhangQ, JeppesenDK, HigginbothamJN, et al.Comprehensive isolation of extracellular vesicles and nanoparticles. Nat Protocols, 2023; 18(5):1462–1487; doi: 10.1038/s41596-023-00811-0.
36.
LaiJJ, ChauZL, ChenSY, et al.Exosome processing and characterization approaches for research and technology development. Adv Sci, 2022; 9(15):e2103222; doi: 10.1002/advs.202103222.
37.
MengW, HeC, HaoY, et al.Prospects and challenges of extracellular vesicle-based drug delivery system: Considering cell source. Drug Deliv, 2020; 27(1):585–598; doi: 10.1080/10717544.2020.1748758.
38.
GaoJ, DongX, WangZ, et al.Generation, purification and engineering of extracellular vesicles and their biomedical applications. Methods (San Diego, Calif.), 2020; 177:114–125; doi: 10.1016/j.ymeth.2019.11.012.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
