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Cited by 94Liver physiology and pathologyExtracellular vesicles in diseaseMicroRNA in disease regulation

Mesenchymal stem cell-derived exosomal miR-27b-3p alleviates liver fibrosis via downregulating YAP/LOXL2 pathway

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Cheng, Fang, Yang, Fuji, Wang, Yanjin, Zhou, Jing, Qian, Hui, Yan, Yongmin·2023·Journal of Nanobiotechnology
DOI 10.1186/s12951-023-01942-yPMC PMC10273609

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Abstract

Lysyl oxidase-like 2 (LOXL2) is an extracellular copper-dependent enzyme that plays a central role in fibrosis by catalyzing the crosslinking and deposition of collagen. Therapeutic LOXL2 inhibition has been shown to suppress liver fibrosis progression and promote its reversal. This study investigates the efficacy and underlying mechanisms of human umbilical cord-derived exosomes (MSC-ex) in LOXL2 inhibition of liver fibrosis. MSC-ex, nonselective LOX inhibitor β-aminopropionitrile (BAPN), or PBS were administered into carbon tetrachloride (CCl4)-induced fibrotic livers. Serum LOXL2 and collagen crosslinking were assessed histologically and biochemically. MSC-ex’s mechanisms on LOXL2 regulation were investigated in human hepatic stellate cell line LX-2. We found that systemic administration of MSC-ex significantly reduced LOXL2 expression and collagen crosslinking, delaying the progression of CCl4-induced liver fibrosis. Mechanically, RNA-sequencing and fluorescence in situ hybridization (FISH) indicated that miR-27b-3p was enriched in MSC-ex and exosomal miR-27b-3p repressed Yes-associated protein (YAP) expression by targeting its 3ʹ untranslated region in LX-2. LOXL2 was identified as a novel downstream target gene of YAP, and YAP bound to the LOXL2 promoter to positively regulate transcription. Additionally, the miR-27b-3p inhibitor abrogated the anti-LOXL2 abilities of MSC-ex and diminished the antifibrotic efficacy. miR-27b-3p overexpression promoted MSC-ex mediated YAP/LOXL2 inhibition. Thus, MSC-ex may suppress LOXL2 expression through exosomal miR-27b-3p mediated YAP down-regulation. The findings here may improve our understanding of MSC-ex in liver fibrosis alleviation and provide new opportunities for clinical treatment.

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  1. [1]Shah PA Patil R Harrison SA NAFLD-related hepatocellular carcinoma: the growing challenge Hepatology 2023 77 1 323 338 10.1002/hep.32542 35478412 PMC9970023 · DOI
  2. [2]Asrani SK Burden of liver diseases in the world J Hepatol 2019 70 1 151 171 10.1016/j.jhep.2018.09.014 30266282 · DOI · Paper page
  3. [3]Zanetto A Hemostasis in cirrhosis: understanding destabilising factors during acute decompensation J Hepatol 2023 78 1037 1047 10.1016/j.jhep.2023.01.010 36708812 · DOI
  4. [4]Dongiovanni P Insulin resistance promotes Lysyl Oxidase Like 2 induction and fibrosis accumulation in non-alcoholic fatty liver disease Clin Sci (Lond) 2017 131 12 1301 1315 10.1042/CS20170175 28468951 · DOI
  5. [6]Gharib AM Magnetic resonance elastography shear wave velocity correlates with liver fibrosis and hepatic venous pressure gradient in adults with advanced liver disease Biomed Res Int 2017 2017 2067479 10.1155/2017/2067479 28480218 PMC5396439 · DOI
  6. [7]Hutchinson JH Small molecule lysyl oxidase-like 2 (LOXL2) inhibitors: the identification of an inhibitor selective for LOXL2 over LOX ACS Med Chem Lett 2017 8 4 423 427 10.1021/acsmedchemlett.7b00014 28435530 PMC5392766 · DOI
  7. [8]Barry-Hamilton V Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment Nat Med 2010 16 9 1009 1017 10.1038/nm.2208 20818376 · DOI · Paper page
  8. [9]Magdaleno F Trebicka J Selective LOXL2 inhibition: potent antifibrotic effects in ongoing fibrosis and fibrosis regression Gut 2017 66 9 1540 1541 10.1136/gutjnl-2016-313621 28246311 · DOI
  9. [10]Ikenaga N Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal Gut 2017 66 9 1697 1708 10.1136/gutjnl-2016-312473 28073888 PMC5561383 · DOI
  10. [14]Meissner EG Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial Liver Int 2016 36 12 1783 1792 10.1111/liv.13177 27232579 PMC5116256 · DOI
  11. [15]Chen W Lysyl oxidase (LOX) family members: rationale and their potential as therapeutic targets for liver fibrosis Hepatology 2020 72 2 729 741 10.1002/hep.31236 32176358 · DOI · Paper page
  12. [16]Gao Y Yin X Ren X Advance of mesenchymal stem cells in chronic end-stage liver disease control Stem Cells Int 2022 2022 1526217 10.1155/2022/1526217 36248254 PMC9568364 · DOI
  13. [17]Xu X Isolation of cancer stem cells from transformed human mesenchymal stem cell line F6 J Mol Med (Berl) 2010 88 11 1181 1190 10.1007/s00109-010-0659-5 20697686 · DOI
  14. [18]Liang W Mesenchymal stem cells as a double-edged sword in tumor growth: focusing on MSC-derived cytokines Cell Mol Biol Lett 2021 26 1 3 10.1186/s11658-020-00246-5 33472580 PMC7818947 · DOI
  15. [19]Psaraki A Extracellular vesicles derived from mesenchymal stem/stromal cells: the regenerative impact in liver diseases Hepatology 2022 75 6 1590 1603 10.1002/hep.32129 34449901 · DOI · Paper page
  16. [21]Yan Y hucMSC exosome-derived GPX1 Is required for the recovery of hepatic oxidant injury Mol Ther 2017 25 2 465 479 10.1016/j.ymthe.2016.11.019 28089078 PMC5368592 · DOI
  17. [22]Jiang W Human umbilical cord MSC-derived exosomes suppress the development of CCl(4)-induced liver injury through antioxidant effect Stem Cells Int 2018 2018 6079642 10.1155/2018/6079642 29686713 PMC5857330 · DOI
  18. [23]Dewidar B TGF-beta in hepatic stellate cell activation and liver fibrogenesis-updated 2019 Cells 2019 8 11 1419 10.3390/cells8111419 31718044 PMC6912224 · DOI · Paper page
  19. [24]Mitten EK Baffy G Mechanotransduction in the pathogenesis of non-alcoholic fatty liver disease J Hepatol 2022 77 6 1642 1656 10.1016/j.jhep.2022.08.028 36063966 · DOI
  20. [25]Findlay A An activity-based bioprobe differentiates a novel small molecule inhibitor from a LOXL2 antibody and provides renewed promise for anti-fibrotic therapeutic strategies Clin Transl Med 2021 11 11 e572 10.1002/ctm2.572 34841699 PMC8571951 · DOI
  21. [26]Liu SB Lysyl oxidase activity contributes to collagen stabilization during liver fibrosis progression and limits spontaneous fibrosis reversal in mice FASEB J 2016 30 4 1599 1609 10.1096/fj.14-268425 26700732 · DOI · Paper page
  22. [27]Iwasaki A Molecular mechanism responsible for fibronectin-controlled alterations in matrix stiffness in advanced chronic liver fibrogenesis J Biol Chem 2016 291 1 72 88 10.1074/jbc.M115.691519 26553870 PMC4697189 · DOI
  23. [28]Todtenhaupt P Mesenchymal stromal cells as a tool to unravel the developmental origins of disease Trends Endocrinol Metab 2022 33 9 614 627 10.1016/j.tem.2022.06.002 35902331 · DOI
  24. [29]Rodriguez-Eguren A Human umbilical cord-based therapeutics: stem cells and blood derivatives for female reproductive medicine Int J Mol Sci 2022 23 24 15942 10.3390/ijms232415942 36555583 PMC9785531 · DOI
  25. [30]Zhang W Comparison of therapeutic effects of mesenchymal stem cells from umbilical cord and bone marrow in the treatment of type 1 diabetes Stem Cell Res Ther 2022 13 1 406 10.1186/s13287-022-02974-1 35941696 PMC9358877 · DOI
  26. [31]Wang ZG Comprehensive proteomic analysis of exosomes derived from human bone marrow, adipose tissue, and umbilical cord mesenchymal stem cells Stem Cell Res Ther 2020 11 1 511 10.1186/s13287-020-02032-8 33246507 PMC7694919 · DOI
  27. [32]Li T Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis Stem Cells Dev 2013 22 6 845 854 10.1089/scd.2012.0395 23002959 PMC3585469 · DOI
  28. [33]Tashkandi MM LOXL2 promotes aggrecan and gender-specific anabolic differences to TMJ cartilage Sci Rep 2020 10 1 20179 10.1038/s41598-020-77178-9 33214607 PMC7678826 · DOI
  29. [34]Lu M Induction of LOX by TGF-beta1/Smad/AP-1 signaling aggravates rat myocardial fibrosis and heart failure IUBMB Life 2019 71 11 1729 1739 10.1002/iub.2112 31317653 · DOI
  30. [36]Tian S Mesenchymal stem cell-derived exosomes protect against liver fibrosis via delivering miR-148a to target KLF6/STAT3 pathway in macrophages Stem Cell Res Ther 2022 13 1 330 10.1186/s13287-022-03010-y 35858897 PMC9297598 · DOI · Paper page

Cited by

Sorted by citations

Authors
Cheng, F., Yang, F., Wang, Y., Zhou, J., Qian, H., & Yan, Y.
Affiliations
Jiangsu University (CN)
Corresponding author
Yan, Yongmin
ORCID
Venue
Journal of Nanobiotechnology
Publisher
Springer Science and Business Media LLC
Published
2023-06-16
Volume
21
Issue
1
Pages
195-195
ISSN
1477-3155 (ISSN-L)
DOI
10.1186/s12951-023-01942-y
PMC
PMC10273609
OpenAlex
W4380985562
Cited by
94
References
6
Citations by year
2026: 28 · 2025: 39 · 2024: 24 · 2023: 3
FWCI
15.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Nanobiotechnology (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Yongmin Yan (82272421)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
Keywords
liver fibrosis, mesenchymal stem cell-derived exosomes, miR-27b-3p, YAP, LOXL2, collagen cross-linking, hepatic stellate cells, carbon tetrachloride-induced fibrosis, exosomal microRNAs, antifibrotic therapy
MeSH terms
Collagen, Humans, Liver Cirrhosis, In Situ Hybridization, Fluorescence, MicroRNAs, Mesenchymal Stem Cells

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