Reports of Biochemistry
and Molecular Biology
Sat, Dec 21, 2024
[Archive]
Volume 12, Issue 2 (Vol.12 No.2 Jul 2023)
rbmb.net 2023, 12(2): 350-358 |
Back to browse issues page
Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
Varjavand P, Hesampour A. The Role of Mesenchymal Stem Cells and Imatinib in the Process of Liver Fibrosis Healing Through CCL2-CCR2 and CX3CL1-CX3CR1 Axes. rbmb.net 2023; 12 (2) :350-358
URL: http://rbmb.net/article-1-1186-en.html
URL: http://rbmb.net/article-1-1186-en.html
Department of Biology, Islamic Azad University Central Tehran Branch, Tehran, Iran.
Abstract: (1199 Views)
Background: Persistent liver damage contributes to the development of liver fibrosis, marked by an accumulation of extracellular matrix. Macrophages play a pivotal role in this process, with the CCL2-CCR2 and CX3CR1-CX3CL1 axes serving as key regulators of macrophage recruitment, liver infiltration, and differentiation. In this study, utilizing a rat model of carbon tetrachloride (CCL4)-induced liver fibrosis, we aimed to investigate the impact of imatinib and bone marrow-derived mesenchymal stem cells (BM-MSCs) on the expression of these axis.
Methods: Sixteen Sprague-Dawley rats were divided into four groups: healthy, liver fibrosis, imatinib-recipient, and BM-MSC-recipient. Treatment effects were evaluated using histopathology and Sirus-red staining. Quantitative real-time PCR was employed to analyze changes in the expression of the genes CCL2, CCR2, CX3CL1, and CX3CR1.
Results: Histopathological assessments revealed the efficacy of imatinib and BM-MSCs in mitigating liver fibrosis. Our findings demonstrated a significant reduction in CCL2 and CCR2 expression in both imatinib and BM-MSCs treatment groups compared to the liver fibrosis group. Conversely, the gene expression of CX3CL1 and CX3CR1 increased in both therapeutic groups compared to the liver fibrosis groups.
Conclusion: Conclusion: The notable decrease in CCL2-CCR2 genes in both therapeutic groups suggests that BM-MSCs and imatinib may contribute to a decline in inflammatory macrophages within the liver. The lower CCL2-CCR2 expression in imatinib-recipient rats indicates better efficacy in modulating the recruitment of inflammatory macrophages. The elevated expression of CX3CL1 in BM-MSC-recipient rats suggests a greater impact on the polarization of LY6Chigh (inflammatory) to LY6Clow (anti-inflammatory) macrophages, warranting further investigation.
Methods: Sixteen Sprague-Dawley rats were divided into four groups: healthy, liver fibrosis, imatinib-recipient, and BM-MSC-recipient. Treatment effects were evaluated using histopathology and Sirus-red staining. Quantitative real-time PCR was employed to analyze changes in the expression of the genes CCL2, CCR2, CX3CL1, and CX3CR1.
Results: Histopathological assessments revealed the efficacy of imatinib and BM-MSCs in mitigating liver fibrosis. Our findings demonstrated a significant reduction in CCL2 and CCR2 expression in both imatinib and BM-MSCs treatment groups compared to the liver fibrosis group. Conversely, the gene expression of CX3CL1 and CX3CR1 increased in both therapeutic groups compared to the liver fibrosis groups.
Conclusion: Conclusion: The notable decrease in CCL2-CCR2 genes in both therapeutic groups suggests that BM-MSCs and imatinib may contribute to a decline in inflammatory macrophages within the liver. The lower CCL2-CCR2 expression in imatinib-recipient rats indicates better efficacy in modulating the recruitment of inflammatory macrophages. The elevated expression of CX3CL1 in BM-MSC-recipient rats suggests a greater impact on the polarization of LY6Chigh (inflammatory) to LY6Clow (anti-inflammatory) macrophages, warranting further investigation.
Type of Article: Original Article |
Subject:
Molecular Biology
Received: 2023/05/30 | Accepted: 2023/11/9 | Published: 2023/12/20
Received: 2023/05/30 | Accepted: 2023/11/9 | Published: 2023/12/20
References
1. Marcellin P, Kutala BK. Liver diseases: A major, neglected global public health problem requiring urgent actions and large‐scale screening. Liver Int. 2018;38:2-6. [DOI:10.1111/liv.13682] [PMID]
2. Schuppan D, Ashfaq-Khan M, Yang AT, Kim YO. Liver fibrosis: Direct antifibrotic agents and targeted therapies. Matrix Biol. 2018;68:435-51. [DOI:10.1016/j.matbio.2018.04.006] [PMID]
3. Sacchi P, Cima S, Corbella M, Comolli G, Chiesa A, Baldanti F, et al. Liver fibrosis, microbial translocation and immune activation markers in HIV and HCV infections and in HIV/HCV co-infection. Dig Liver Dis. 2015;47(3):218-25. [DOI:10.1016/j.dld.2014.11.012] [PMID]
4. Khomich O, Ivanov A V, Bartosch B. Metabolic hallmarks of hepatic stellate cells in liver fibrosis. Cells. 2019;9(1):24. [DOI:10.3390/cells9010024] [PMID] []
5. Poulsen KL, Ross CKC-D, Chaney JK, Nagy LE. Role of the chemokine system in liver fibrosis: a narrative review. Dig Med Res. 2022;5:30-30. [DOI:10.21037/dmr-21-87] [PMID] []
6. Karlmark KR, Weiskirchen R, Zimmermann HW, Gassler N, Ginhoux F, Weber C, et al. Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology. 2009;50(1):261-74. [DOI:10.1002/hep.22950] [PMID]
7. Tacke F. Targeting hepatic macrophages to treat liver diseases. J Hepatol. 2017;66(6):1300-12. [DOI:10.1016/j.jhep.2017.02.026] [PMID]
8. Papadopoulos C, Mimidis K, Papazoglou D, Kolios G, Tentes I, Anagnostopoulos K. Red blood cell-conditioned media from non-alcoholic fatty liver disease patients contain increased MCP1 and induce TNF-α release. Reports Biochem Mol Biol. 2022;11(1):54. [DOI:10.52547/rbmb.11.1.54] [PMID] []
9. Triantafyllou E, Woollard KJ, McPhail MJW, Antoniades CG, Possamai LA. The role of monocytes and macrophages in acute and acute-on-chronic liver failure. Front Immunol. 2018; 9: 2948. Epub 2019/01/09. doi: 10.3389/fimmu. 2018.02948 30619308; 2018. [DOI:10.3389/fimmu.2018.02948] [PMID] []
10. Baghaei K, Mazhari S, Tokhanbigli S, Parsamanesh G, Alavifard H, Schaafsma D, et al. Therapeutic potential of targeting regulatory mechanisms of hepatic stellate cell activation in liver fibrosis. Drug Discov Today. 2022;27(4):1044-61. [DOI:10.1016/j.drudis.2021.12.012] [PMID]
11. Hayatbakhsh MM, Shabgah AG, Pishgouyi S, Afshari JT, Zeidabadi H, Mohammadi M. The serum levels of CCL2 and CCL16 expression in patients with irritable bowel syndrome. Reports Biochem Mol Biol. 2019;8(1):9.
12. Karlmark KR, Zimmermann HW, Roderburg C, Gassler N, Wasmuth HE, Luedde T, et al. The fractalkine receptor CX3CR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes. Hepatology. 2010;52(5):1769-82. [DOI:10.1002/hep.23894] [PMID]
13. Aoyama T, Inokuchi S, Brenner DA, Seki E. CX3CL1‐CX3CR1 interaction prevents carbon tetrachloride‐induced liver inflammation and fibrosis in mice. Hepatology. 2010;52(4):1390-400. [DOI:10.1002/hep.23795] [PMID] []
14. El-Mezayen NS, El-Hadidy WF, El-Refaie WM, Shalaby TI, Khattab MM, El-Khatib AS. Hepatic stellate cell-targeted imatinib nanomedicine versus conventional imatinib: a novel strategy with potent efficacy in experimental liver fibrosis. J Control release. 2017;266:226-37. [DOI:10.1016/j.jconrel.2017.09.035] [PMID]
15. Khalil MR, El-Demerdash RS, Elminshawy HH, Mehanna ET, Mesbah NM, Abo-Elmatty DM. Therapeutic effect of bone marrow mesenchymal stem cells in a rat model of carbon tetrachloride induced liver fibrosis. Biomed J. 2021;44(5):598-610. [DOI:10.1016/j.bj.2020.04.011] [PMID] []
16. Zhao D-C, Lei J-X, Chen R, Yu W-H, Zhang X-M, Li S-N, et al. Bone marrow-derived mesenchymal stem cells protect against experimental liver fibrosis in rats. World J Gastroenterol WJG. 2005;11(22):3431. [DOI:10.3748/wjg.v11.i22.3431] [PMID] []
17. Mazhari S, Gitiara A, Baghaei K, Hatami B, Rad RE, Asadirad A, et al. Therapeutic potential of bone marrow-derived mesenchymal stem cells and imatinib in a rat model of liver fibrosis. Eur J Pharmacol. 2020;882:173263. [DOI:10.1016/j.ejphar.2020.173263] [PMID]
18. Baghaei K, Hashemi SM, Tokhanbigli S, Rad AA, Assadzadeh-Aghdaei H, Sharifian A, et al. Isolation, differentiation, and characterization of mesenchymal stem cells from human bone marrow. Gastroenterol Hepatol from bed to bench. 2017;10(3):208.
19. Tacke F. Functional role of intrahepatic monocyte subsets for the progression of liver inflammation and liver fibrosis in vivo. In: Fibrogenesis & tissue repair. Springer; 2012. p. 1-8. [DOI:10.1186/1755-1536-5-S1-S27] [PMID] []
20. Weiskirchen R, Tacke F. Liver fibrosis: from pathogenesis to novel therapies. Dig Dis. 2016;34(4):410-22. [DOI:10.1159/000444556] [PMID]
21. Mansour MF, Greish SM, El-Serafi AT, Abdelall H, El-Wazir YM. Therapeutic potential of human umbilical cord derived mesenchymal stem cells on rat model of liver fibrosis. Am J Stem Cells. 2019;8(1):7.
22. Yoshiji H, Noguchi R, Kuriyama S, Ikenaka Y, Yoshii J, Yanase K, et al. Imatinib mesylate (STI-571) attenuates liver fibrosis development in rats. Am J Physiol Liver Physiol. 2005;288(5):G907-13. [DOI:10.1152/ajpgi.00420.2004] [PMID]
23. Sakaida I, Terai S, Yamamoto N, Aoyama K, Ishikawa T, Nishina H, et al. Transplantation of bone marrow cells reduces CCl4‐induced liver fibrosis in mice. Hepatology. 2004;40(6):1304-11. [DOI:10.1002/hep.20452] [PMID]
24. Gorji SM, Malekshah AAK, Hashemi-Soteh MB, Rafiei A, Parivar K, Aghdami N. Effect of mesenchymal stem cells on doxorubicin-induced fibrosis. Cell J. 2012;14(2):142.
25. Akhmetshina A, Venalis P, Dees C, Busch N, Zwerina J, Schett G, et al. Treatment with imatinib prevents fibrosis in different preclinical models of systemic sclerosis and induces regression of established fibrosis. Arthritis Rheum. 2009;60(1):219-24. [DOI:10.1002/art.24186] [PMID]
26. Kuo W-L, Yu M-C, Lee J-F, Tsai C-N, Chen T-C, Chen M-F. Imatinib mesylate improves liver regeneration and attenuates liver fibrogenesis in CCL4-treated mice. J Gastrointest Surg. 2012;16(2):361-9. [DOI:10.1007/s11605-011-1764-7] [PMID]
27. Scott CL, Zheng F, De Baetselier P, Martens L, Saeys Y, De Prijck S, et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat Commun. 2016;7(1):1-10. [DOI:10.1038/ncomms10321] [PMID] []
28. Baeck C, Wehr A, Karlmark KR, Heymann F, Vucur M, Gassler N, et al. Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. Gut. 2012;61(3):416-26. [DOI:10.1136/gutjnl-2011-300304] [PMID]
29. Puengel T, Krenkel O, Kohlhepp M, Lefebvre E, Luedde T, Trautwein C, et al. Differential impact of the dual CCR2/CCR5 inhibitor cenicriviroc on migration of monocyte and lymphocyte subsets in acute liver injury. PLoS One. 2017;12(9):e0184694. [DOI:10.1371/journal.pone.0184694] [PMID] []
30. Kreutzman A, Yadav B, Brummendorf TH, Gjertsen BT, Hee Lee M, Janssen J, et al. Immunological monitoring of newly diagnosed CML patients treated with bosutinib or imatinib first-line. Oncoimmunology. 2019;8(9):e1638210. [DOI:10.1080/2162402X.2019.1638210] [PMID] []
31. Zhang M, Liu H, Huang K, Peng Y, Tao Y, Zhao C, et al. Fuzheng Huayu recipe prevented and treated CCl4-induced mice liver fibrosis through regulating polarization and chemotaxis of intrahepatic macrophages via CCL2 and CX3CL1. Evidence-Based Complement Altern Med. 2020;2020 :8591892. [DOI:10.1155/2020/8591892] [PMID] []
Send email to the article author
| Rights and permissions | |
 |
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
