Pathomechanism of Liver Fibrosis and Mesenchymal Stem Cells in its Resolution Process

Anggun Lestary Husein; Isabella Kurnia Liem

doi:10.3889/oamjms.2023.11342

Authors

Anggun Lestary Husein 1Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Master’s Programme in Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Department of Anatomy, Faculty of Medicine, Pattimura University, Mollucas, Indonesia https://orcid.org/0000-0001-6867-7841
Isabella Kurnia Liem 1Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia https://orcid.org/0000-0002-0138-2659

DOI:

https://doi.org/10.3889/oamjms.2023.11342

Keywords:

mesenchymal stem cells, MSCs, liver fibrosis, liver fibrosis resolution, Hepatic Stellate Cells, HSCs

Abstract

Liver fibrosis is a disease process that, without adequate treatment, can lead to liver failure and can be life-threatening. This disease is reversible and appropriate therapy can prevent further liver damage. Liver transplant therapy is the only treatment for an end-stage liver disease that works, but it has various obstacles and limitations in its implementation. Therefore, nowadays, mesenchymal stem cells (MSCs) have become a hope of therapy for liver fibrosis. Our literature review describes the pathomechanism of liver fibrosis and the steps of its resolution, accompanied by the possible role of MSCs in supporting the process. The activation of several complex pathways regulates liver fibrosis, and its resolution, involving Transforming Growth Factor (TGF)-β, signal transducer and activator of transcription-3, and Wnt/β-catenin signaling is involved in Hepatic Stellate Cells (HSCs) activation, which are precursors of myofibroblasts (MFs) and causes fibrosis. The presence of the High-mobility group box-1 pathway, which also induces the production of proinflammatory cytokines and the role of matrix metalloproteinases (MMPs)/tissue Inhibitors of MMPs s and Syndecan-1, is incorporated into the extracellular matrix (ECM). In repairing liver damage, four steps of liver fibrosis resolution are required, such as preventing further damage, restoring the intrahepatic balance of inflammation, removing and inactivating MFs, and ECM degradation associated with arresting the eight pathways of the fibrosis mechanism. MSCs can help resolve liver fibrosis and speed up wound healing, increase hepatocyte survival, and suppress HSCs activation by blocking fibrosis mechanism pathways such as TGF-β and pro-inflammatory factors such as tumor necrosis factor-alpha, interferon-gamma, IL-6, IL-17, and IL-23, in addition to an elevated level of an anti-inflammatory factor like IL-10.

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References

Salas-Villalobos TB, Lozano-Sepúlveda SA, Rincón- Sánchez AR, Govea-Salas M, Rivas-Estilla AM. Mechanisms involved in liver damage resolution after hepatitis C virus clearance. Med Univ. 2017;19(75):100-7. https://doi.org/10.1016/j.rmu.2017.05.005 DOI: https://doi.org/10.1016/j.rmu.2017.05.005

Cheng JY, Wong GL. Advances in the diagnosis and treatment of liver fibrosis. Hepatoma Res. 2017;3(8):156-69. https://doi. org/10.20517/2394-5079.2017.27 DOI: https://doi.org/10.20517/2394-5079.2017.27

Koyama Y, Xu J, Liu X, Brenner DA. New developments on the treatment of liver fibrosis. Dig Dis. 2016;34(5):589-96. https://doi.org/10.1159/000445269 PMid:27332862 DOI: https://doi.org/10.1159/000445269

Sun H, Shi C, Ye Z, Yao B, Li C, Wang X, et al. The role of mesenchymal stem cells in liver injury. Cell Biol Int.

;46(4):501-11. https://doi.org/10.1002/cbin.11725 PMid:34882906 DOI: https://doi.org/10.1002/cbin.11725

Sa’dyah NA, Putra A, Dirja BT, Hidayah N, Azzahara SY, Irawan RC. Suppression of transforming growth factor-β by mesenchymal stem-cells accelerates liver regeneration in liver fibrosis animal model. Univ Med. 2021;40(1):29-35. https://doi.org/10.18051/UnivMed.2021.v40.29-35 DOI: https://doi.org/10.18051/UnivMed.2021.v40.29-35

Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatol. 2019;70(1):151-71. https://doi.org/10.1016/j.jhep.2018.09.014 PMid:30266282 DOI: https://doi.org/10.1016/j.jhep.2018.09.014

Wang J, Sun M, Liu W, Li Y, Li M. Stem cell-based therapies for liver diseases: An overview and update. Tissue Eng Regen Med. 2019;16(2):107-18. https://doi.org/10.1007/s13770-019-00178-y PMid:30989038 DOI: https://doi.org/10.1007/s13770-019-00178-y

Sun YM, Chen SY, You H. Regression of liver fibrosis: Evidence and challenges. Chin Med J (Engl). 2020;133(14):1696-702. https://doi.org/10.1097/CM9.0000000000000835 PMid:32568866 DOI: https://doi.org/10.1097/CM9.0000000000000835

Wang R, Song F, Li S, Wu B, Gu Y, Yuan Y. Salvianolic acid A attenuates CCl4-induced liver fibrosis by regulating the PI3K/ AKT/mTOR, Bcl-2/Bax and caspase-3/cleaved caspase-3 signaling pathways. Drug Des Devel Ther. 2019;13:1889-900. https://doi.org/10.2147/DDDT.S194787 PMid:31213776 DOI: https://doi.org/10.2147/DDDT.S194787

Hawxby A, Rubin EM, Piao D, Hawxby A, Wright H, Rubin EM. Perspective review on solid-organ transplant: Needs in point- of-care optical biomarkers. J Biomed Opt. 2018;23(08):1-14. https://doi.org/10.1117/1.JBO.23.8.080601 PMid:30160078 DOI: https://doi.org/10.1117/1.JBO.23.8.080601

Cao Y, Ji C, Lu L. Mesenchymal stem cell therapy for liver fibrosis/cirrhosis. Ann Transl Med. 2020;8(8):562. https://doi.org/10.21037/atm.2020.02.119 PMid:32775363 DOI: https://doi.org/10.21037/atm.2020.02.119

Lukomska B, Stanaszek L, Zuba-Surma E, Legosz P, Sarzynska S, Drela K. Challenges and controversies in human mesenchymal stem cell therapy. Stem Cells Int. 2019;2019:9628536. https://doi.org/10.1155/2019/9628536 PMid:31093291 DOI: https://doi.org/10.1155/2019/9628536

Sepulveda-Crespo D, Resino S, Martinez I. Strategies targeting the innate immune response for the treatment of hepatitis C virus-associated liver fibrosis. Drugs. 2021;81(4):419-43. https://doi.org/10.1007/s40265-020-01458-x PMid:33400242 DOI: https://doi.org/10.1007/s40265-020-01458-x

Hu C, Wu Z, Li L. Mesenchymal stromal cells promote liver regeneration through regulation of immune cells. Int J Biol Sci.

;16(5):893-903. https://doi.org/10.7150/ijbs.39725 PMid:2071558 DOI: https://doi.org/10.7150/ijbs.39725

Nathwani R, Mullish B, Kockerling D, Forlano R, Manousou P, Dhar A. A review of liver fibrosis and emerging therapies. EMJ. 2019;4(4):105-16. https://doi.org/10.33590/emj/10310892 DOI: https://doi.org/10.33590/emj/10310892

Zhangdi HJ, Su SB, Wang F, Liang ZY, Yan YD, Qin SY, et al. Crosstalk network among multiple inflammatory mediators in liver fibrosis. World J Gastroenterol. 2019;25(33):4835-49. https://doi.org/10.3748/wjg.v25.i33.4835 PMid:31543677 DOI: https://doi.org/10.3748/wjg.v25.i33.4835

Gupta P, Sata TN, Yadav AK, Mishra A, Vats N, Hossain MM, et al. TGF-β induces liver fibrosis via miRNA-181a-mediated down regulation of augmenter of liver regeneration in hepatic stellate cells. PLoS One. 2019;14(6):e0214534. https://doi.org/10.1371/journal.pone.0214534 PMid:31166951 DOI: https://doi.org/10.1371/journal.pone.0214534

Shi X, Young CD, Zhou H, Wang X. Transforming growth factor-β signaling in fibrotic diseases and cancer-associated fibroblasts. Biomolecules. 2020;10(12):1666. https://doi.org/10.3390/biom10121666 PMid:33322749 DOI: https://doi.org/10.3390/biom10121666

Hermansyah D, Putra A, Muhar AM, Retnaningsih, Wirastuti K, Dirja BT. Mesenchymal stem cells suppress TGF-β release to decrease α-SMA expression in ameliorating CCl4-induced liver fibrosis. Med Arch. 2021;75(1):16-22. https://doi.org/10.5455/medarh.2021.75.16-22 PMid:34012193 DOI: https://doi.org/10.5455/medarh.2021.75.16-22

Kanmani P, Kim H. Probiotics counteract the expression of hepatic profibrotic genes via the attenuation of TGF-β/ SMAD signaling and autophagy in hepatic stellate cells. PLoS One. 2022;17(1):e0262767. https://doi.org/10.1371/journal.pone.0262767 PMid:35051234 DOI: https://doi.org/10.1371/journal.pone.0262767

Bharadwaj U, Kasembeli MM, Robinson P, Tweardy DJ. Targeting Janus kinases and signal transducer and activator of transcription 3 to treat inflammation, fibrosis, and cancer: Rationale, progress, and caution. Pharmacol Rev. 2020;72(2):486-526. https://doi.org/10.1124/pr.119.018440 PMid:32198236 DOI: https://doi.org/10.1124/pr.119.018440

Zhao J, Qi YF, Yu YR. STAT3: A key regulator in liver fibrosis. Ann Hepatol. 2021;21:100224. https://doi.org/10.1016/j.aohep.2020.06.010 PMid:32702499 DOI: https://doi.org/10.1016/j.aohep.2020.06.010

Xiong Y, Torsoni AS, Wu F, Shen H, Liu Y, Zhong X, et al. Hepatic NF-kb-inducing kinase (NIK) suppresses mouse liver regeneration in acute and chronic liver diseases. Elife. 2018;7:e34152. https://doi.org/10.7554/eLife.34152 PMid:30070632 DOI: https://doi.org/10.7554/eLife.34152

Sun L, Gong W, Shen Y, Liang L, Zhang X, Li T, et al. IL-17A- producing γδT cells promote liver pathology in acute murine schistosomiasis. Parasit Vectors. 2020;13(1):334. https://doi.org/10.1186/s13071-020-04200-4 PMid:32611373 DOI: https://doi.org/10.1186/s13071-020-04200-4

Nishikawa K, Osawa Y, Kimura K. Wnt/β-catenin signaling as a potential target for the treatment of liver cirrhosis using antifibrotic drugs. Int J Mol Sci. 2018;19(10):3103. https://doi.org/10.3390/ijms19103103 PMid:30308992 DOI: https://doi.org/10.3390/ijms19103103

Kelly DA. Hepatocellular death: Apoptosis, autophagy, necrosis and necroptosis. In: Radu-Ionita F, Pyrsopoulos NT, Bontas E, Tintoiu IC, editors. Liver Diseases a Multidisciplinary Textbook. Romania: Springer; 2020. p. 37-51. DOI: https://doi.org/10.1007/978-3-030-24432-3_4

Hu SJ, Jiang SS, Zhang J, Luo D, Yu B, Yang LY, et al. Effects of apoptosis on liver aging. World J Clin Cases. 2019;7(6):691-704. https://doi.org/10.12998/wjcc.v7.i6.691 PMid:30968034 DOI: https://doi.org/10.12998/wjcc.v7.i6.691

Jun JI, Lau LF. Resolution of organ fibrosis. J Clin Invest. 2018;128(1):97-107. https://doi.org/10.1172/JCI93563 PMid:29293097 DOI: https://doi.org/10.1172/JCI93563

Geervliet E, Bansal R. Matrix metalloproteinases as potential biomarkers and therapeutic targets in liver diseases. Cells. 2020;9(5):1212. https://doi.org/10.3390/cells9051212 PMid:32414178 DOI: https://doi.org/10.3390/cells9051212

Charchanti A, Kanavaros P, Koniaris E, Kataki A, Glantzounis G, Agnantis NJ, et al. Expression of Syndecan-1 in chronic liver diseases: Correlation with hepatic fibrosis. In Vivo. 2021;35(1):333-9. https://doi.org/10.21873/invivo.12264 PMid:33402482 DOI: https://doi.org/10.21873/invivo.12264

Regős E, Abdelfattah HH, Reszegi A, Szilák L, Werling K, Szabó G, et al. Syndecan-1 inhibits early stages of liver fibrogenesis by interfering with TGFβ1 action and upregulating MMP14. Matrix Biol. 2018;68-69:474-89. https://doi.org/10.1016/j.matbio.2018.02.008 PMid:29454902 DOI: https://doi.org/10.1016/j.matbio.2018.02.008

Gopal S. Syndecans in inflammation at a glance. Front Immunol. 2020;11:227. https://doi.org/10.3389/fimmu.2020.00227 PMid:32133006 DOI: https://doi.org/10.3389/fimmu.2020.00227

Ni YA, Chen H, Nie H, Zheng B, Gong Q. HMGB1: An overview of its roles in the pathogenesis of liver disease. J Leukoc Biol. 2021;110(5):987-98. https://doi.org/10.1002/JLB.3MR0121-277R PMid:33784425 DOI: https://doi.org/10.1002/JLB.3MR0121-277R

Inkaya AC, Demir NA, Kolgelier S, Sumer S, Demir LS, Ural O, et al. Is serum high-mobility group box 1 (HMGB-1) level correlated with liver fibrosis in chronic hepatitis B? Medicine (Baltimore). 2017;96(36):e7547. https://doi.org/10.1097/MD.0000000000007547 PMid:28885322 DOI: https://doi.org/10.1097/MD.0000000000007547

Lee WJ, Song SY, Roh H, Ahn HM, Na Y, Kim J, et al. Profibrogenic effect of high-mobility group box Protein-1 in human dermal fibroblasts and its excess in keloid tissues. Sci Rep. 2018;8(1):8434. https://doi.org/10.1038/s41598-018-26501-6 PMid:29849053 DOI: https://doi.org/10.1038/s41598-018-26501-6

Nimbalkar VV, Shelke RP, Kadu UE, Gaikwad PM. A review on liver fibrosis: It’s pathogenesis, resolution and experimental models. IJPPR Human. 2018;12(4):94-114.

Cordero-Espinoza L, Huch M. The balancing act of the liver: Tissue regeneration versus fibrosis. J Clin Invest. 2018;128(1):85-96. https://doi.org/10.1172/JCI93562 PMid:29293095 DOI: https://doi.org/10.1172/JCI93562

Tacke F, Trautwein C. Mechanisms of liver fibrosis resolution. J Hepatol. 2015;63(4):1038-9. https://doi.org/10.1016/j.jhep.2015.03.039 PMid:26232376 DOI: https://doi.org/10.1016/j.jhep.2015.03.039

Hu C, Wu Z, Li L. Pre-treatments enhance the therapeutic effects of mesenchymal stem cells in liver diseases. J Cell Mol Med. 2020;24(1):40-9. https://doi.org/10.1111/jcmm.14788 PMid:31691463 DOI: https://doi.org/10.1111/jcmm.14788

Rodríguez-Fuentes DE, Fernández-Garza LE, Samia-Meza JA, Barrera-Barrera SA, Caplan AI, Barrera- Saldaña HA. Mesenchymal stem cells current clinical applications: A systematic review. Arch Med Res. 2021;52(1):93-101. https://doi.org/10.1016/j.arcmed.2020.08.006 PMid:32977984 DOI: https://doi.org/10.1016/j.arcmed.2020.08.006

Andrzejewska A, Lukomska B, Janowski M. Concise review: Mesenchymal stem cells: From roots to boost. Stem Cells.

;37(7):855-64. https://doi.org/10.1002/stem.3016 PMid:30977255 DOI: https://doi.org/10.1002/stem.3016

Rowland AL, Miller D, Berglund A, Schnabel LV, Levine GJ, Antczak DF, et al. Cross-matching of allogeneic mesenchymal stromal cells eliminates recipient immune targeting. Stem Cells Transl Med. 2021;10(5):694-710. https://doi.org/10.1002/sctm.20-0435 PMid:33369287 DOI: https://doi.org/10.1002/sctm.20-0435

Bavarsad SS, Jalali MT, Nejad DB, Alypoor B, Rezaei HB, Mohammadtaghvaei N. TGFβ1-pretreated exosomes of Wharton jelly mesenchymal stem cell as a therapeutic strategy for improving liver fibrosis. Hepat Mon. 2022;22(1):1-12. https://doi.org/10.5812/hepatmon-123416 DOI: https://doi.org/10.5812/hepatmon-123416

Yang Y, Zhao Y, Zhang L, Zhang F, Li L. The application of mesenchymal stem cells in the treatment of liver diseases: Mechanism, efficacy, and safety issues. Front Med (Lausanne). 2021;8:655268. https://doi.org/10.3389/fmed.2021.655268 PMid:34136500 DOI: https://doi.org/10.3389/fmed.2021.655268

Liem IK, Oktavina R, Zakiyah, Anggraini D, Deraya IE, Kodariah R, et al. Intravenous injection of umbilical cord-derived mesenchymal stem cells improved regeneration of rat liver after 2aaf/ccl4-induced injury. Online J Biol Sci. 2021;21(2):317-26. https://doi.org/10.3844/ojbsci.2021.317.326 DOI: https://doi.org/10.3844/ojbsci.2021.317.326

De Luna-Saldivar MM, Marino-Martinez IA, Franco-Molina MA, Rivera-Morales LG, Alarcón-Galván G, Cordero-Pérez P, et al. Advantages of adipose tissue stem cells over CD34+ mobilization to decrease hepatic fibrosis in Wistar rats. Ann Hepatol. 2019;18(4):620-6. https://doi.org/10.1016/j.aohep.2018.12.005 PMid:31147180 DOI: https://doi.org/10.1016/j.aohep.2018.12.005

Chen ZK, Chen DZ, Cai C, Jin LL, Xu J, Tu YL, et al. BMSCs attenuate hepatic fibrosis in autoimmune hepatitis through regulation of LMO7-AP1-TGFβ signaling pathway. Eur Rev Med Pharmacol Sci. 2021;25(3):1600-11. https://doi.org/10.26355/eurrev_202102_24870 PMid:33629329

Yang N, Ma W, Ke Y, Liu H, Chu J, Sun L, et al. Transplantation of adipose-derived stem cells ameliorates Echinococcus multilocularis-induced liver fibrosis in mice. PLoS Negl Trop Dis. 2022;16(1):e0010175. https://doi.org/10.1371/journal.pntd.0010175 PMid:35100287 DOI: https://doi.org/10.1371/journal.pntd.0010175