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Cited by 144Extracellular vesicles in diseaseMesenchymal stem cell researchLiver physiology and pathology

Mesenchymal stem cell-derived exosomes protect against liver fibrosis via delivering miR-148a to target KLF6/STAT3 pathway in macrophages

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Tian, Siyuan, Zhou, Xia, Zhang, Miao, Cui, Lina, Li, Bo, Liu, Yansheng, Su, Rui, Sun, Keshuai +10 more·2022·Stem Cell Research & Therapy
DOI 10.1186/s13287-022-03010-yPMC PMC9297598
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Abstract

BACKGROUND: Despite emerging evidence on the therapeutic potential of mesenchymal stem cells (MSCs) for liver fibrosis, the underlying mechanisms remain unclear. At present, MSC-derived exosomes (MSC-EXOs) are widely accepted as crucial messengers for intercellular communication. This study aimed to explore the therapeutic effects of MSC-EXOs on liver fibrosis and identify the mechanisms underlying the action of MSC-EXOs. METHODS: Carbon tetrachloride was used to induce a liver fibrosis model, which was intravenously administered with MSCs or MSC-EXOs to assess treatment efficacy. The resulting histopathology, fibrosis degree, inflammation and macrophage polarization were analyzed. RAW264.7 and BMDM cells were used to explore the regulatory effects of MSC-EXOs on macrophage polarization. Then, the critical miRNA mediating the therapeutic effects of MSC-EXOs was screened via RNA sequencing and validated experimentally. Furthermore, the target mRNA and downstream signaling pathways were elucidated by luciferase reporter assay, bioinformatics analysis and western blot. RESULTS: MSCs alleviated liver fibrosis largely depended on their secreted exosomes, which were visualized to circulate into liver after transplantation. In addition, MSC-EXOs were found to modulate macrophage phenotype to regulate inflammatory microenvironment in liver and repair the injury. Mechanically, RNA-sequencing illustrates that miR-148a, enriched in the MSC-EXOs, targets Kruppel-like factor 6 (KLF6) to suppress pro-inflammatory macrophages and promote anti-inflammatory macrophages by inhibiting the STAT3 pathway. Administration of miR-148a-enriched MSC-EXOs or miR-148a agomir shows potent ameliorative effects on liver fibrosis. CONCLUSIONS: These findings suggest that MSC-EXOs protect against liver fibrosis via delivering miR-148a that regulates intrahepatic macrophage functions through KLF6/STAT3 signaling and provide a potential therapeutic target for liver fibrosis.

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  • MSC-Exo-derived miR-148a promotes the polarization of M1 towards M2 both in vitro and in mouse models via the KLF6/STAT3 pathway.

    “Similarly, MSC-Exo-derived miR-148a promoted the polarization of M1 towards M2 both in vitro and in mouse models via the KLF6/STAT3 pathway [210].”

    From Mechanisms, efficacy, and future perspectives of cellular-based therapies for liver fibrosis/cirrhosis: focusing on mesenchymal stromal cells (2025) · cites this paper as [210]

    The Results sections on miR-148a-mediated polarization and KLF6 report an M1-to-M2 shift in cultured macrophages and evidence implicating KLF6/STAT3. The in vivo Results section reports a similar shift in fibrotic mice treated with MSC exosomes, but does not establish that exosomal miR-148a caused that shift through KLF6/STAT3 in those mice. The paper therefore supports the in vitro mechanism and the mouse-level exosome effect, but not their full combination as stated. (LLM, conf=0.87)

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References 49 · Cited by 144

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  1. [1]Schuppan D Kim Y Evolving therapies for liver fibrosis J Clin Investig 2013 123 1887 1901 10.1172/JCI66028 23635787 PMC3635731 · DOI
  2. [2]Global, regional, and national age-sex-specific mortality and life expectancy, 1950–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet (London, England) 2018; 392:1684–1735. PMC6227504 30496102
  3. [3]Tsochatzis E Bosch J Burroughs A Liver cirrhosis Lancet 2014 383 1749 1761 10.1016/S0140-6736(14)60121-5 24480518 · DOI
  4. [4]Wu G Shi H Che M Huang M Wei Q Feng B Ma Y Wang L Jiang B Wang Y Recovery of paralyzed limb motor function in canine with complete spinal cord injury following implantation of MSC-derived neural network tissue Biomaterials 2018 181 15 34 10.1016/j.biomaterials.2018.07.010 30071379 · DOI
  5. [6]Duijvestein M Vos A Roelofs H Wildenberg M Wendrich B Verspaget H Kooy-Winkelaar E Koning F Zwaginga J Fidder H Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn's disease: results of a phase I study Gut 2010 59 1662 1669 10.1136/gut.2010.215152 20921206 · DOI · Paper page
  6. [7]Hashmi S Ahmed M Murad M Litzow M Adams R Ball L Prasad V Kebriaei P Ringden O Survival after mesenchymal stromal cell therapy in steroid-refractory acute graft-versus-host disease: systematic review and meta-analysis Lancet Haematol 2016 3 e45 52 10.1016/S2352-3026(15)00224-0 26765648 · DOI
  7. [8]An S Jang Y Lim H Han J Lee J Lee G Park J Park S Kim J Do B Milk fat globule-EGF factor 8, secreted by mesenchymal stem cells, protects against liver fibrosis in mice Gastroenterology 2017 152 1174 1186 10.1053/j.gastro.2016.12.003 27956229 · DOI · Paper page
  8. [9]Wang M Zhang M Fu L Lin J Zhou X Zhou P Huang P Hu H Han Y Liver-targeted delivery of TSG-6 by calcium phosphate nanoparticles for the management of liver fibrosis Theranostics 2020 10 36 49 10.7150/thno.37301 31903104 PMC6929629 · DOI
  9. [10]Ren G Zhang L Zhao X Xu G Zhang Y Roberts A Zhao R Shi Y Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide Cell Stem Cell 2008 2 141 150 10.1016/j.stem.2007.11.014 18371435 · DOI · Paper page
  10. [11]Rani S Ryan A Griffin M Ritter T Mesenchymal stem cell-derived extracellular vesicles: toward cell-free therapeutic applications Mole ther J Am Soc Gene Ther 2015 23 812 823 10.1038/mt.2015.44 PMC4427881 25868399 · DOI
  11. [13]Valadi H Ekström K Bossios A Sjöstrand M Lee J Lötvall J Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells Nat Cell Biol 2007 9 654 659 10.1038/ncb1596 17486113 · DOI · Paper page
  12. [14]Liu X Pan Q Cao H Xin F Zhao Z Yang R Zeng J Zhou H Fan J Lipotoxic hepatocyte-derived exosomal microRNA 192–5p activates macrophages through rictor/akt/forkhead box transcription factor O1 signaling in nonalcoholic fatty liver disease Hepatology 2020 72 454 469 10.1002/hep.31050 31782176 PMC10465073 · DOI
  13. [15]Ge L Xun C Li W Jin S Liu Z Zhuo Y Duan D Hu Z Chen P Lu M Extracellular vesicles derived from hypoxia-preconditioned olfactory mucosa mesenchymal stem cells enhance angiogenesis via miR-612 J Nanobiotechnol 2021 19 380 10.1186/s12951-021-01126-6 PMC8607643 34802444 · DOI
  14. [16]Phan J Kumar P Hao D Gao K Farmer D Wang A Engineering mesenchymal stem cells to improve their exosome efficacy and yield for cell-free therapy J Extracell vesicles 2018 7 1522236 10.1080/20013078.2018.1522236 30275938 PMC6161586 · DOI
  15. [17]Xiao C Wang K Xu Y Hu H Zhang N Wang Y Zhong Z Zhao J Li Q Zhu D Transplanted mesenchymal stem cells reduce autophagic flux in infarcted hearts via the exosomal transfer of miR-125b Circ Res 2018 123 564 578 10.1161/CIRCRESAHA.118.312758 29921652 · DOI
  16. [18]Zhou X Cui L Zhou X Yang Q Wang L Guo G Hou Y Cai W Han Z Shi Y Han Y Induction of hepatocyte-like cells from human umbilical cord-derived mesenchymal stem cells by defined microRNAs J Cell Mol Med 2017 21 881 893 10.1111/jcmm.13027 27874233 PMC5387126 · DOI
  17. [19]Muratori L Muratori P Lanzoni G Ferri S Lenzi M Application of the 2010 American Association for the study of liver diseases criteria of remission to a cohort of Italian patients with autoimmune hepatitis Hepatology 2010 52 5 1857 10.1002/hep.23924 20931560 · DOI
  18. [20]Wai C Greenson J Fontana R Kalbfleisch J Marrero J Conjeevaram H Lok A A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C Hepatology 2003 38 518 526 10.1053/jhep.2003.50346 12883497 · DOI · Paper page
  19. [24]Betel D Wilson M Gabow A Marks D Sander C The microRNA.org resource: targets and expression Nucleic Acids Res 2008 10.1093/nar/gkm995 18158296 PMC2238905 · DOI
  20. [25]Wang X miRDB: a microRNA target prediction and functional annotation database with a wiki interface RNA 2008 14 1012 1017 10.1261/rna.965408 18426918 PMC2390791 · DOI
  21. [26]Lewis B Burge C Bartel D Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets Cell 2005 120 15 20 10.1016/j.cell.2004.12.035 15652477 · DOI · Paper page
  22. [27]Chi S Zang J Mele A Darnell R Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps Nature 2009 460 479 486 10.1038/nature08170 19536157 PMC2733940 · DOI · Paper page
  23. [28]Katsuda T Kosaka N Takeshita F Ochiya T The therapeutic potential of mesenchymal stem cell-derived extracellular vesicles Proteomics 2013 13 1637 1653 10.1002/pmic.201200373 23335344 · DOI
  24. [29]Trajkovic K Hsu C Chiantia S Rajendran L Wenzel D Wieland F Schwille P Brügger B Simons M Ceramide triggers budding of exosome vesicles into multivesicular endosomes Science 2008 319 1244 1247 10.1126/science.1153124 18309083 · DOI
  25. [31]Wang C Ma C Gong L Guo Y Fu K Zhang Y Zhou H Li Y Macrophage polarization and its role in liver disease Front Immunol 2021 12 803037 10.3389/fimmu.2021.803037 34970275 PMC8712501 · DOI
  26. [32]Wynn T Barron L Macrophages: master regulators of inflammation and fibrosis Semin Liver Dis 2010 30 245 257 10.1055/s-0030-1255354 20665377 PMC2924662 · DOI · Paper page
  27. [33]Lee C Chen Y Wu H Lee O Historical perspectives and advances in mesenchymal stem cell research for the treatment of liver diseases Gastroenterology 2018 154 46 56 10.1053/j.gastro.2017.09.049 29107021 · DOI
  28. [34]Dwyer BJ Macmillan MT Brennan PN Forbes SJ Cell therapy for advanced liver diseases: repair or rebuild – ScienceDirect J Hepatol 2021 74 185 199 10.1016/j.jhep.2020.09.014 32976865 · DOI · Paper page
  29. [35]Baz HE, Demerdash Z, Kamel M, Atta S, Raafat I. ARTICLETransplant of Hepatocytes, Undifferentiated Mesenchymal Stem Cells, and In Vitro Hepatocyte-Differentiated Mesenchymal Stem Cells in a Chronic Liver Failure Experimental Model: A Comparative Study. Experimental and clinical transplantation: official journal of the Middle East Society for Organ Transplantation 2017. 28585911
  30. [36]Shi Y Wang Y Li Q Liu K Hou J Shao C Ying W Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases Nat Rev Nephrol 2018 10.1038/s41581-018-0023-5 29895977 · DOI · Paper page
  31. [37]Caplan AI Correa D The MSC: an injury drugstore Cell Stem Cell 2011 9 11 15 10.1016/j.stem.2011.06.008 21726829 PMC3144500 · DOI · Paper page
  32. [38]Rong X Liu J Yao X Jiang T Wang Y Human bone marrow mesenchymal stem cells-derived exosomes alleviate liver fibrosis through the Wnt/β-catenin pathway Stem Cell Res Ther 2019 10.1186/s13287-019-1204-2 30885249 PMC6421647 · DOI
  33. [39]Li T Yan Y Wang B Qian H Zhang X Shen L Wang M Zhou Y Zhu W Li W Xu W Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis Stem Cells Develop 2013 22 845 854 10.1089/scd.2012.0395 PMC3585469 23002959 · DOI
  34. [40]Duffield JS Forbes SJ Constandinou CM Clay S Iredale JP Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair J Clin Investig 2005 115 56 65 10.1172/JCI200522675 15630444 PMC539199 · DOI · Paper page
  35. [41]Murray PJ Allen JE Biswas SK Fisher EA Gilroy DW Goerdt S Gordon S Hamilton JA Ivashkiv LB Lawrence T Locati M Macrophage activation and polarization: nomenclature and experimental guidelines Immunity 2014 41 339 340 10.1016/j.immuni.2014.07.009 PMC4123412 25035950 · DOI
  36. [42]Phinney DG Giuseppe M Njah J Sala E Shiva S Croix C Stolz DB Watkins SC Di YP Leikauf GD Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs Nat Commun 2015 6 8472 10.1038/ncomms9472 26442449 PMC4598952 · DOI · Paper page
  37. [43]Zheng D Li Z Wei X Liu R Shen A He D Tang C Wu Z Role of miR-148a in mitigating hepatic ischemia-reperfusion injury by repressing the TLR4 signaling pathway via targeting CaMKIIα in vivo and in vitro Cell Physiol Biochem 2018 49 2060 2072 10.1159/000493716 30244246 · DOI
  38. [44]Liu J Ding D Jiang Z Du T Zhaohui J Long non-coding RNA CCAT1/miR-148a/PKCζ prevents cell migration of prostate cancer by altering macrophage polarization Prostate 2018 10.1002/pros.23716 30221381 · DOI
  39. [45]Mcconnell BB Yang VW Mammalian krüppel-like factors in health and diseases Physiol Rev 2010 90 1337 1381 10.1152/physrev.00058.2009 20959618 PMC2975554 · DOI
  40. [46]Zhang Y Li C Guan C Zhou B Xu Y MiR-181d-5p targets KLF6 to improve ischemia/reperfusion-induced AKI through effects on renal function, apoptosis, and inflammation Front Physiol 2020 11 510 10.3389/fphys.2020.00510 32581828 PMC7295155 · DOI
  41. [47]Kim GD Ng HP Chan ER Mahabeleshwar GH Kruppel-like factor 6 promotes macrophage inflammatory and hypoxia response FASEB J 2020 10.1096/fj.201902221R 31908054 PMC7774039 · DOI
  42. [48]Kim GD Ng HP Patel N Mahabeleshwar GH Kruppel-like factor 6 and miR-223 signaling axis regulates macrophage-mediated inflammation FASEB J 2019 10.1096/fj.201900867RR 31262200 PMC6766645 · DOI
  43. [49]Date D Das R Narla G Simon DI Jain MK Mahabeleshwar GH Kruppel-like transcription factor 6 regulates inflammatory macrophage polarization J Biol Chem 2014 289 10318 10329 10.1074/jbc.M113.526749 24385430 PMC4036156 · DOI

Authors
Tian, S., Zhou, X., Zhang, M., Cui, L., Li, B., Liu, Y., Su, R., Sun, K., Hu, Y., Yang, F., Xuan, G., Ma, S., Zheng, X., Zhou, X., Guo, C., Shang, Y., Wang, J., & Han, Y.
Affiliations
Xijing Hospital (CN)
Corresponding author
  • Shang, Yulong
  • Wang, Jingbo
  • Han, Ying
ORCID
Venue
Stem Cell Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2022-07-20
Volume
13
Issue
1
Pages
330-330
ISSN
1757-6512 (ISSN-L)
DOI
10.1186/s13287-022-03010-y
PMC
PMC9297598
OpenAlex
W4285891338
Cited by
144
References
49
Citations by year
2026: 31 · 2025: 48 · 2024: 32 · 2023: 30 · 2022: 3
FWCI
9.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Stem Cell Research & Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81770569, 81870421)
  • International Cooperation and Exchange of the National Natural Science Foundation of China (81820108005)
  • National Key Research and Development Program of China (2020YFA0710803)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
mesenchymal stem cell-derived exosomes, liver fibrosis, miR-148a, KLF6, STAT3 signaling, macrophage polarization, carbon tetrachloride-induced liver injury, exosome-mediated intercellular communication, anti-inflammatory macrophages, liver inflammation
MeSH terms
Kruppel-Like Factor 6, Humans, Liver Cirrhosis, Macrophages, MicroRNAs, STAT3 Transcription Factor, Exosomes, Mesenchymal Stem Cells

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