Mesenchymal stem cells versus their extracellular vesicles in treatment of liver fibrosis: Is it possible to compare?
Main Article Content
Abstract
Liver fibrosis (LF) is a worldwide health problem that is associated with a range of complications and high mortality. Due to the scarcity of liver donors, mesenchymal stem cell (MSC) therapy emerged as an alternative therapeutic strategy. However, it is widely accepted that most of the transplanted MSCs exhibit their therapeutic impact mainly via a bystander paracrine (medicinal) capacity. In addition to their secretory proteins, MSCs also produce various types of extracellular vesicles (EVs) that are classified into three main subtypes: microvesicles, exosomes and apoptotic bodies. Thanks to their peculiar cargo composition (e.g., proteins, lipids, and nucleic acids), EVs serve as an advantageous candidate for cell-free therapy. Recently, MSC-derived EVs (MSC-EVs) have gained the podium due to their regenerative and immunomodulatory effect. In mitigation/treatment of LF, a plethora of recent studies have shown the anti-inflammatory, anti-fibrotic and cytoprotective effects of both MSCs and MSC-EVs in various in vitro and in vivo models of LF. However, despite the limited evidence, we sought in this mini review to sort out the established data and formulate several challenging questions that must be answered to pave the way for further clinical applications. One of the major questions to ask is “Which is the best therapeutic approach, MSCs or MSC-EVs?” We tried to highlight how difficult it might be to compare the two approaches while our understanding of both candidates is still deficient. Among the major obstacles against such comparison is the inaccurate equivalent dose determination, the unknown in vivo behavior, and the undetermined lifespan/fate of each. Currently, the fields of MSCs and MSC-EVs seem to be rich in ideas but lacking in appropriate technologies to test these ideas. Nevertheless, continuous efforts are likely to help resolve some of the challenges listed here.
Keywords:
Mesenchymal stem cells, Extracellular vesicles, Exosomes, Cirrhosis, Cell-free therapy
Article Details
How to Cite
ATTIA, Noha et al.
Mesenchymal stem cells versus their extracellular vesicles in treatment of liver fibrosis: Is it possible to compare?.
Medical Research Archives, [S.l.], v. 9, n. 2, feb. 2021.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2318>. Date accessed: 26 apr. 2024.
doi: https://doi.org/10.18103/mra.v9i2.2318.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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32. Motawi TM, Atta HM, Sadik NA, Azzam M. The therapeutic effects of bone marrow-derived mesenchymal stem cells and simvastatin in a rat model of liver fibrosis. Cell biochemistry and biophysics. 2014;68(1):111-125.
33. Mohamed HE, Elswefy SE, Rashed LA, Younis NN, Shaheen MA, Ghanim AM. Bone marrow-derived mesenchymal stem cells effectively regenerate fibrotic liver in bile duct ligation rat model. Experimental Biology and Medicine. 2016;241(6):581-591.
34. Lei J, Chai Y, Xiao J, et al. Antifibrotic potential of bone marrow‑derived mesenchymal stem cells in biliary atresia mice. Molecular medicine reports. 2018;18(4):3983-3988.
35. Idriss NK, Sayyed HG, Osama A, Sabry D. Treatment efficiency of different routes of bone marrow-derived mesenchymal stem cell injection in rat liver fibrosis model. Cellular Physiology and Biochemistry. 2018;48(5):2161-2171.
36. Watanabe Y, Tsuchiya A, Seino S, et al. Mesenchymal stem cells and induced bone marrow‐derived macrophages synergistically improve liver fibrosis in mice. Stem cells translational medicine. 2019;8(3):271-284.
37. Huang B, Cheng X, Wang H, et al. Mesenchymal stem cells and their secreted molecules predominantly ameliorate fulminant hepatic failure and chronic liver fibrosis in mice respectively. Journal of translational medicine. 2016;14(1):45.
38. Duman DG, Zibandeh N, Ugurlu MU, et al. Mesenchymal stem cells suppress hepatic fibrosis accompanied by expanded intrahepatic natural killer cells in rat fibrosis model. Molecular biology reports. 2019;46(3):2997-3008.
39. Hwang S, Hong HN, Kim HS, et al. Hepatogenic differentiation of mesenchymal stem cells in a rat model of thioacetamide‐induced liver cirrhosis. Cell biology international. 2012;36(3):279-288.
40. Tsai PC, Fu TW, Chen YMA, et al. The therapeutic potential of human umbilical mesenchymal stem cells from Wharton's jelly in the treatment of rat liver fibrosis. Liver transplantation. 2009;15(5):484-495.
41. Chai N-L, Zhang X-B, Chen S-W, Fan K-X, Linghu E-Q. Umbilical cord-derived mesenchymal stem cells alleviate liver fibrosis in rats. World journal of gastroenterology. 2016;22(26):6036.
42. Rustad KC, Gurtner GC. Mesenchymal Stem Cells Home to Sites of Injury and Inflammation. Advances in wound care. 2012;1(4):147-152.
43. Squires JE, Soltys KA, McKiernan P, et al. Clinical hepatocyte transplantation: what is next? 2017;4(4):280-289.
44. Veziroglu EM, Mias GIJFiG. Characterizing extracellular vesicles and their diverse RNA contents. 2020;11.
45. Li T, Yan Y, Wang B, et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. 2013;22(6):845-854.
46. Qu Y, Zhang Q, Cai X, 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(10):2491-2502.
47. Ohara M, Ohnishi S, Hosono H, et al. Extracellular Vesicles from Amnion-Derived Mesenchymal Stem Cells Ameliorate Hepatic Inflammation and Fibrosis in Rats. Stem Cells International. 2018;2018:3212643.
48. Rong X, Liu J, Yao X, Jiang T, Wang Y, Xie F. Human bone marrow mesenchymal stem cells-derived exosomes alleviate liver fibrosis through the Wnt/β-catenin pathway. Stem Cell Res Ther. 2019;10(1):98-98.
49. Sabry D, Mohamed A, Monir M, Ibrahim HA. The Effect of Mesenchymal Stem Cells Derived Microvesicles on the Treatment of Experimental CCL4 Induced Liver Fibrosis in Rats. Int J Stem Cells. 2019;12(3):400-409.
50. Mardpour S, Hassani SN, Mardpour S, et al. Extracellular vesicles derived from human embryonic stem cell-MSCs ameliorate cirrhosis in thioacetamide-induced chronic liver injury. Journal of cellular physiology. 2018;233(12):9330-9344.
51. Mardpour S, Ghanian MH, Sadeghi-abandansari H, et al. Hydrogel-Mediated Sustained Systemic Delivery of Mesenchymal Stem Cell-Derived Extracellular Vesicles Improves Hepatic Regeneration in Chronic Liver Failure. ACS Applied Materials & Interfaces. 2019;11(41):37421-37433.
52. Fiore E, Domínguez LM, 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 Therapy. 2020;27(1):62-73.
2. Miao Z, Jin J, Chen L, et al. Isolation of mesenchymal stem cells from human placenta: comparison with human bone marrow mesenchymal stem cells. 2006;30(9):681-687.
3. Kern S, Eichler H, Stoeve J, Klüter H, Bieback KJSc. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. 2006;24(5):1294-1301.
4. Roubelakis MG, Pappa KI, Bitsika V, et al. Molecular and proteomic characterization of human mesenchymal stem cells derived from amniotic fluid: comparison to bone marrow mesenchymal stem cells. 2007;16(6):931-952.
5. Alviano F, Fossati V, Marchionni C, et al. Term amniotic membrane is a high throughput source for multipotent mesenchymal stem cells with the ability to differentiate into endothelial cells in vitro. 2007;7(1):1-14.
6. Rodríguez‐Lozano FJ, Bueno C, Insausti CL, et al. Mesenchymal stem cells derived from dental tissues. 2011;44(9):800-806.
7. Meng X, Ichim TE, Zhong J, et al. Endometrial regenerative cells: a novel stem cell population. 2007;5(1):1-10.
8. Ulrich D, Muralitharan R, Gargett CEJEoobt. Toward the use of endometrial and menstrual blood mesenchymal stem cells for cell-based therapies. 2013;13(10):1387-1400.
9. Fernández M, Minguell JJ. Human mesenchymal stem cells from peripheral blood. In: Google Patents; 2001.
10. in't Anker PS, Scherjon SA, Kleijburg‐van der Keur C, et al. Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. 2004;22(7):1338-1345.
11. Rotter N, Oder J, Schlenke P, et al. Isolation and characterization of adult stem cells from human salivary glands. 2008;17(3):509-518.
12. Al-Nbaheen M, Ali D, Bouslimi A, et al. Human stromal (mesenchymal) stem cells from bone marrow, adipose tissue and skin exhibit differences in molecular phenotype and differentiation potential. 2013;9(1):32-43.
13. Citro L, Naidu S, Hassan F, et al. Comparison of human induced pluripotent stem-cell derived cardiomyocytes with human mesenchymal stem cells following acute myocardial infarction. 2014;9(12):e116281.
14. Honmou O, Houkin K, Matsunaga T, et al. Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. 2011;134(6):1790-1807.
15. Kharaziha P, Hellström PM, Noorinayer B, et al. Improvement of liver function in liver cirrhosis patients after autologous mesenchymal stem cell injection: a phase I–II clinical trial. 2009;21(10):1199-1205.
16. Mazzini L, Mareschi K, Ferrero I, et al. Autologous mesenchymal stem cells: clinical applications in amyotrophic lateral sclerosis. 2006;28(5):523-526.
17. Le Blanc K, Frassoni F, Ball L, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. 2008;371(9624):1579-1586.
18. Franquesa M, Hoogduijn MJ, Reinders ME, et al. Mesenchymal Stem Cells in Solid Organ Transplantation (MiSOT) 4th meeting: Lessons learned from first clinical trials. 2013;96(3):234.
19. Mehanna RA, Nabil I, Attia N, et al. The effect of bone marrow-derived mesenchymal stem cells and their conditioned media topically delivered in fibrin glue on chronic wound healing in rats. 2015;2015.
20. Attia N, Mashal M, Grijalvo S, et al. Stem cell-based gene delivery mediated by cationic niosomes for bone regeneration. 2018;14(2):521-531.
21. Attia N, Mashal M. Mesenchymal Stem Cells: The Past Present and Future. 2020.
22. Attia N, Santos E, Abdelmouty H, et al. Behaviour and ultrastructure of human bone marrow-derived mesenchymal stem cells immobilised in alginate-poly-l-lysine-alginate microcapsules. 2014;31(6):579-589.
23. Rostom DM, Attia N, Khalifa HM, Abou Nazel MW, El Sabaawy EAJTE, Medicine R. The Therapeutic Potential of Extracellular Vesicles Versus Mesenchymal Stem Cells in Liver Damage. 2020.
24. Aziz MA, Atta H, Mahfouz S, et al. Therapeutic potential of bone marrow-derived mesenchymal stem cells on experimental liver fibrosis. Clinical biochemistry. 2007;40(12):893-899.
25. Kamel MM, Baz HGE, Demerdash Z, et al. Cord blood-derived mesenchymal stem cells with hepatogenic differentiation potential ameliorate chronic liver affection in experimental models. Advances in Clinical and Experimental Medicine. 2018;27(10):1329-1339.
26. Yu F, Ji S, Su L, et al. Adipose-derived mesenchymal stem cells inhibit activation of hepatic stellate cells in vitro and ameliorate rat liver fibrosis in vivo. Journal of the Formosan Medical Association. 2015;114(2):130-138.
27. Zhang G-Z, Sun H-C, Zheng L-B, Guo J-B, Zhang X-L. In vivo hepatic differentiation potential of human umbilical cord-derived mesenchymal stem cells: Therapeutic effect on liver fibrosis/cirrhosis. World journal of gastroenterology. 2017;23(46):8152.
28. Li Q, Zhou X, Shi Y, et al. In vivo tracking and comparison of the therapeutic effects of MSCs and HSCs for liver injury. PloS one. 2013;8(4):e62363.
29. Khalifa YH, Mourad GM, Stephanos WM, Omar SA, Mehanna RA. Bone Marrow-Derived Mesenchymal Stem Cell Potential Regression of Dysplasia Associating Experimental Liver Fibrosis in Albino Rats. BioMed Research International. 2019;2019.
30. Zhang L, Zhou D, Li J, et al. Effects of Bone Marrow-Derived Mesenchymal Stem Cells on Hypoxia and the Transforming Growth Factor beta 1 (TGFβ-1) and SMADs Pathway in a Mouse Model of Cirrhosis. Medical science monitor: international medical journal of experimental and clinical research. 2019;25:7182.
31. Raafat N, Aal SMA, Abdo FK, El Ghonaimy NM. Mesenchymal stem cells: in vivo therapeutic application ameliorates carbon tetrachloride induced liver fibrosis in rats. The international journal of biochemistry & cell biology. 2015;68:109-118.
32. Motawi TM, Atta HM, Sadik NA, Azzam M. The therapeutic effects of bone marrow-derived mesenchymal stem cells and simvastatin in a rat model of liver fibrosis. Cell biochemistry and biophysics. 2014;68(1):111-125.
33. Mohamed HE, Elswefy SE, Rashed LA, Younis NN, Shaheen MA, Ghanim AM. Bone marrow-derived mesenchymal stem cells effectively regenerate fibrotic liver in bile duct ligation rat model. Experimental Biology and Medicine. 2016;241(6):581-591.
34. Lei J, Chai Y, Xiao J, et al. Antifibrotic potential of bone marrow‑derived mesenchymal stem cells in biliary atresia mice. Molecular medicine reports. 2018;18(4):3983-3988.
35. Idriss NK, Sayyed HG, Osama A, Sabry D. Treatment efficiency of different routes of bone marrow-derived mesenchymal stem cell injection in rat liver fibrosis model. Cellular Physiology and Biochemistry. 2018;48(5):2161-2171.
36. Watanabe Y, Tsuchiya A, Seino S, et al. Mesenchymal stem cells and induced bone marrow‐derived macrophages synergistically improve liver fibrosis in mice. Stem cells translational medicine. 2019;8(3):271-284.
37. Huang B, Cheng X, Wang H, et al. Mesenchymal stem cells and their secreted molecules predominantly ameliorate fulminant hepatic failure and chronic liver fibrosis in mice respectively. Journal of translational medicine. 2016;14(1):45.
38. Duman DG, Zibandeh N, Ugurlu MU, et al. Mesenchymal stem cells suppress hepatic fibrosis accompanied by expanded intrahepatic natural killer cells in rat fibrosis model. Molecular biology reports. 2019;46(3):2997-3008.
39. Hwang S, Hong HN, Kim HS, et al. Hepatogenic differentiation of mesenchymal stem cells in a rat model of thioacetamide‐induced liver cirrhosis. Cell biology international. 2012;36(3):279-288.
40. Tsai PC, Fu TW, Chen YMA, et al. The therapeutic potential of human umbilical mesenchymal stem cells from Wharton's jelly in the treatment of rat liver fibrosis. Liver transplantation. 2009;15(5):484-495.
41. Chai N-L, Zhang X-B, Chen S-W, Fan K-X, Linghu E-Q. Umbilical cord-derived mesenchymal stem cells alleviate liver fibrosis in rats. World journal of gastroenterology. 2016;22(26):6036.
42. Rustad KC, Gurtner GC. Mesenchymal Stem Cells Home to Sites of Injury and Inflammation. Advances in wound care. 2012;1(4):147-152.
43. Squires JE, Soltys KA, McKiernan P, et al. Clinical hepatocyte transplantation: what is next? 2017;4(4):280-289.
44. Veziroglu EM, Mias GIJFiG. Characterizing extracellular vesicles and their diverse RNA contents. 2020;11.
45. Li T, Yan Y, Wang B, et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. 2013;22(6):845-854.
46. Qu Y, Zhang Q, Cai X, 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(10):2491-2502.
47. Ohara M, Ohnishi S, Hosono H, et al. Extracellular Vesicles from Amnion-Derived Mesenchymal Stem Cells Ameliorate Hepatic Inflammation and Fibrosis in Rats. Stem Cells International. 2018;2018:3212643.
48. Rong X, Liu J, Yao X, Jiang T, Wang Y, Xie F. Human bone marrow mesenchymal stem cells-derived exosomes alleviate liver fibrosis through the Wnt/β-catenin pathway. Stem Cell Res Ther. 2019;10(1):98-98.
49. Sabry D, Mohamed A, Monir M, Ibrahim HA. The Effect of Mesenchymal Stem Cells Derived Microvesicles on the Treatment of Experimental CCL4 Induced Liver Fibrosis in Rats. Int J Stem Cells. 2019;12(3):400-409.
50. Mardpour S, Hassani SN, Mardpour S, et al. Extracellular vesicles derived from human embryonic stem cell-MSCs ameliorate cirrhosis in thioacetamide-induced chronic liver injury. Journal of cellular physiology. 2018;233(12):9330-9344.
51. Mardpour S, Ghanian MH, Sadeghi-abandansari H, et al. Hydrogel-Mediated Sustained Systemic Delivery of Mesenchymal Stem Cell-Derived Extracellular Vesicles Improves Hepatic Regeneration in Chronic Liver Failure. ACS Applied Materials & Interfaces. 2019;11(41):37421-37433.
52. Fiore E, Domínguez LM, 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 Therapy. 2020;27(1):62-73.