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Human umbilical cord perivascular cells-derived extracellular vesicles mediate the transfer of IGF-I to the liver and ameliorate hepatic fibrogenesis in mice

Gene Therapy volume 27, pages 62–73 (2020)Cite this article

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Abstract

Extracellular vesicles (EVs) can mediate mesenchymal stromal cells (MSCs) paracrine effects. We aimed to evaluate the therapeutic potential of human umbilical cord perivascular cells (HUCPVCs) engineered to produce Insulin Growth Factor like-I (IGF-I) in experimental liver fibrosis and the role of EVs in this effect. HUCPVCs were engineered to produce human IGF-I (AdhIGF-I) or green fluorescence protein (AdGFP) using adenoviruses, and EVs were isolated from their conditioned medium (CM). In vitro effects of CM and EVs on hepatic stellate cells and hepatic macrophages were studied. Cells or EVs-based treatments were evaluated in thioacetamide-induced liver fibrosis in mice. The application of AdhIGF-I-HUCPVCs resulted in a further amelioration of liver fibrosis when compared to AdGFP-HUCPVCs and saline. Similarly, treatment with AdhIGF-I-HUCPVCs-derived EVs resulted in a reduction of collagen deposition and gene expression of the fibrogenic related molecules TGF-β1, α-SMA, and COL1A2. In vitro incubation of hepatic stellate cells with EVs-AdhIGF-I-HUCPVCs significantly reduced activation of fibrogenic cells. In addition, EVs-AdhIGF-I-HUCPVCs trigger hepatic macrophages to switch their phenotype towards anti-inflammatory phagocytes, which might be involved in the antifibrotic effect. Consistently, high levels of IGF-I were observed within EVs-AdhIGF-I-HUCPVCs but not in controls EVs. Our results showed that hIGF-I carrying EVs could mediate the paracrine mechanism by which AdhIGF-I-HUCPVCs reduce liver fibrosis.

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References

  1. Lee YA, Wallace MC, Friedman SL. Pathobiology of liver fibrosis: a translational success story. Gut. 2015;64:830–41.

    Article  CAS  Google Scholar 

  2. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115:209–18.

    Article  CAS  Google Scholar 

  3. Bonefeld K, Moller S. Insulin-like growth factor-I and the liver. Liver Int. 2011;31:911–9.

    Article  CAS  Google Scholar 

  4. Castilla-Cortazar I, Garcia M, Muguerza B, Quiroga J, Perez R, Santidrian S, et al. Hepatoprotective effects of insulin-like growth factor I in rats with carbon tetrachloride-induced cirrhosis. Gastroenterology. 1997;113:1682–91.

    Article  CAS  Google Scholar 

  5. Conchillo M, de Knegt RJ, Payeras M, Quiroga J, Sangro B, Herrero JI, et al. Insulin-like growth factor I (IGF-I) replacement therapy increases albumin concentration in liver cirrhosis: results of a pilot randomized controlled clinical trial. J Hepatol. 2005;43:630–6.

    Article  CAS  Google Scholar 

  6. Sobrevals L, Enguita M, Quiroga J, Prieto J, Fortes P. Insulin-like growth factor I (IGF-I) expressed from an AAV1 vector leads to a complete reversion of liver cirrhosis in rats. PLoS ONE. 2016;11:e0162955.

    Article  Google Scholar 

  7. Sobrevals L, Rodriguez C, Romero-Trevejo JL, Gondi G, Monreal I, Paneda A, et al. Insulin-like growth factor I gene transfer to cirrhotic liver induces fibrolysis and reduces fibrogenesis leading to cirrhosis reversion in rats. Hepatology. 2010;51:912–21.

    CAS  PubMed  Google Scholar 

  8. Ramachandran P, Iredale JP. Macrophages: central regulators of hepatic fibrogenesis and fibrosis resolution. J Hepatol. 2012;56:1417–9.

    Article  Google Scholar 

  9. Tacke F, Zimmermann HW. Macrophage heterogeneity in liver injury and fibrosis. J Hepatol. 2014;60:1090–6.

    Article  CAS  Google Scholar 

  10. Fiore EJ, Dominguez LM, Bayo J, Garcia MG, Mazzolini GD. Taking advantage of the potential of mesenchymal stromal cells in liver regeneration: cells and extracellular vesicles as therapeutic strategies. World J Gastroenterol. 2018;24:2427–40.

    Article  CAS  Google Scholar 

  11. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315–7.

    Article  CAS  Google Scholar 

  12. Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood. 2007;110:3499–506.

    Article  CAS  Google Scholar 

  13. Bayo J, Marrodan M, Aquino JB, Silva M, Garcia MG, Mazzolini G. The therapeutic potential of bone marrow-derived mesenchymal stromal cells on hepatocellular carcinoma. Liver Int. 2013;34:330–42.

    Article  Google Scholar 

  14. Fiore EJ, Mazzolini G, Aquino JB. Mesenchymal stem/stromal cells in liver fibrosis: recent findings, old/new caveats and future perspectives. Stem Cell Rev. 2015;11:586–97.

    Article  CAS  Google Scholar 

  15. Hass R, Kasper C, Bohm S, Jacobs R. Different populations and sources of human mesenchymal stem cells (MSC): A comparison of adult and neonatal tissue-derived MSC. Cell Commun Signal. 2011;9:12.

    Article  CAS  Google Scholar 

  16. Sarugaser R, Lickorish D, Baksh D, Hosseini MM, Davies JE. Human umbilical cord perivascular (HUCPV) cells: a source of mesenchymal progenitors. Stem Cells. 2005;23:220–9.

    Article  Google Scholar 

  17. Bayo J, Fiore E, Aquino JB, Malvicini M, Rizzo M, Peixoto E, et al. Human umbilical cord perivascular cells exhibited enhanced migration capacity towards hepatocellular carcinoma in comparison with bone marrow mesenchymal stromal cells: a role for autocrine motility factor receptor. Biomed Res Int. 2014;2014:837420.

    Article  Google Scholar 

  18. Bayo J, Fiore E, Aquino JB, Malvicini M, Rizzo M, Peixoto E, et al. Increased migration of human mesenchymal stromal cells by autocrine motility factor (AMF) resulted in enhanced recruitment towards hepatocellular carcinoma. PLoS ONE. 2014;9:e95171.

    Article  Google Scholar 

  19. Fiore EJ, Bayo JM, Garcia MG, Malvicini M, Lloyd R, Piccioni F, et al. Mesenchymal stromal cells engineered to produce IGF-I by recombinant adenovirus ameliorate liver fibrosis in mice. Stem Cells Dev. 2015;24:791–801.

    Article  CAS  Google Scholar 

  20. Fiore E, Malvicini M, Bayo J, Peixoto E, Atorrasagasti C, Sierra R, et al. Involvement of hepatic macrophages in the antifibrotic effect of IGF-I-overexpressing mesenchymal stromal cells. Stem Cell Res Ther. 2016;7:172.

    Article  Google Scholar 

  21. Kusuma GD, Carthew J, Lim R, Frith JE. Effect of the microenvironment on mesenchymal stem cell paracrine signaling: opportunities to engineer the therapeutic effect. Stem Cells Dev. 2017;26:617–31.

    Article  CAS  Google Scholar 

  22. Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2:569–79.

    Article  CAS  Google Scholar 

  23. Lotvall J, Hill AF, Hochberg F, Buzas EI, Di Vizio D, Gardiner C, et al. Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J Extracell Vesicles. 2014;3:26913.

    Article  Google Scholar 

  24. Ha D, Yang N, Nadithe V. Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges. Acta Pharmaceutica Sinica B. 2016;6:287–96.

    Article  Google Scholar 

  25. Armstrong JP, Holme MN, Stevens MM. Re-engineering extracellular vesicles as smart nanoscale therapeutics. ACS Nano. 2017;11:69–83.

    Article  CAS  Google Scholar 

  26. Liu Q, Yu Z, Yuan S, Xie W, Li C, Hu Z, et al. Circulating exosomal microRNAs as prognostic biomarkers for non-small-cell lung cancer. Oncotarget. 2017;8:13048–58.

    PubMed  Google Scholar 

  27. Kim DK, Nishida H, An SY, Shetty AK, Bartosh TJ, Prockop DJ. Chromatographically isolated CD63+CD81+ extracellular vesicles from mesenchymal stromal cells rescue cognitive impairments after TBI. Proc Natl Acad Sci USA. 2016;113:170–5.

    Article  CAS  Google Scholar 

  28. Braid LR, Hu WG, Davies JE, Nagata LP. Engineered mesenchymal cells improve passive immune protection against lethal venezuelan equine encephalitis virus exposure. Stem Cells Transl Med. 2016;5:1026–35.

    Article  CAS  Google Scholar 

  29. Li T, Yan Y, Wang B, Qian H, Zhang X, Shen L, et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells Dev. 2013;22:845–54.

    Article  CAS  Google Scholar 

  30. Chen L, Xiang B, Wang X, Xiang C. Exosomes derived from human menstrual blood-derived stem cells alleviate fulminant hepatic failure. Stem Cell Res Ther. 2017;8:9.

    Article  Google Scholar 

  31. Haga H, Yan IK, Takahashi K, Matsuda A, Patel T. Extracellular vesicles from bone marrow-derived mesenchymal stem cells improve survival from lethal hepatic failure in mice. Stem Cells Transl Med. 2017;6:1262–72.

    Article  CAS  Google Scholar 

  32. Tan CY, Lai RC, Wong W, Dan YY, Lim SK, Ho HK. Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models. Stem Cell Res Ther. 2014;5:76.

    Article  Google Scholar 

  33. Lou G, Yang Y, Liu F, Ye B, Chen Z, Zheng M, et al. MiR-122 modification enhances the therapeutic efficacy of adipose tissue-derived mesenchymal stem cells against liver fibrosis. J Cell Mol Med. 2017;21:2963–73.

    Article  CAS  Google Scholar 

  34. Qu Y, Zhang Q, Cai X, Li F, Ma Z, Xu M, et al. Exosomes derived from miR-181-5p-modified adipose-derived mesenchymal stem cells prevent liver fibrosis via autophagy activation. J Cell Mol Med. 2017;21:2491–502.

    Article  CAS  Google Scholar 

  35. Keerthikumar S, Chisanga D, Ariyaratne D, Al Saffar H, Anand S, Zhao K, et al. ExoCarta: a web-based compendium of exosomal cargo. J Mol Biol. 2016;428:688–92.

    Article  CAS  Google Scholar 

  36. Treacy O, Ryan AE, Heinzl T, O’Flynn L, Cregg M, Wilk M, et al. Adenoviral transduction of mesenchymal stem cells: in vitro responses and in vivo immune responses after cell transplantation. PLoS ONE. 2012;7:e42662.

    Article  CAS  Google Scholar 

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Acknowledgements

We acknowledge Paula Rosello, Alejandrina Real, Mariana Banis, and Guillermo Gaston for technical support.

Funding

This work was supported in part by grants from the Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT) (PICT 2015 N° 2036; PICTO 2016-0101), Fundación Allende, Fundación Alberto Roemmers, PUE0102 (CONICET), and Universidad Austral.

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Author notes

  1. These authors contributed equally: Esteban Fiore, Luciana M. Domínguez

Authors and Affiliations

  1. Gene Therapy Laboratory, Instituto de Investigaciones en Medicina Traslacional, CONICET-Universidad Austral, Av. Pte. Perón 1500 (B1629AHJ) Derqui-Pilar, Buenos Aires, Argentina

    Esteban Fiore, Luciana M. Domínguez, Juan Bayo, Mariana Malvicini, Catalina Atorrasagasti, Marcelo Rodriguez, María José Cantero, Mariana García & Guillermo Mazzolini

  2. CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina

    Esteban Fiore, Juan Bayo, Mariana Malvicini, Catalina Atorrasagasti, Mariana García, Gustavo Yannarelli & Guillermo Mazzolini

  3. Laboratorio de Regulación Génica y Células Madre. Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMeTTyB), Universidad Favaloro-CONICET, Buenos Aires, Argentina

    Gustavo Yannarelli

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  1. Esteban Fiore
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Correspondence to Guillermo Mazzolini.

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Fiore, E., Domínguez, L.M., Bayo, J. et al. Human umbilical cord perivascular cells-derived extracellular vesicles mediate the transfer of IGF-I to the liver and ameliorate hepatic fibrogenesis in mice. Gene Ther 27, 62–73 (2020). https://doi.org/10.1038/s41434-019-0102-7

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  • DOI: https://doi.org/10.1038/s41434-019-0102-7

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