Immunomodulatory Effects of Stem Cell Therapy in Liver Fibrosis: A Systematic Review
-
Sahar Rahimi
,
Ali Derakhshani
,
Atena Alifarsangi
,
Seyedeh Mahdieh Khoshnazar
,
Nader Shahrokhi
,
Mohammad Hosein Shakeri
Abstract
Liver fibrosis is known as a condition characterized by chronic inflammation and excessive extracellular matrix deposition that causes cirrhosis and liver failure. Stem cell therapy is a promising strategy for the management of liver fibrosis because it not only improves tissue regeneration but also modulates by immunomodulatory mechanisms.
This systematic review aimed to evaluate the immunoregulatory effects of stem cells in both experimental models and clinical studies of liver fibrosis. A total of 29 studies were included, comprising several stem cell sources, including bone marrow-derived mesenchymal stem cells (BM-MSCs), umbilical cord-derived MSCs (UC-MSCs), adipose tissue-derived MSCs (AT-MSCs), and stem cells from human exfoliated deciduous teeth (SHED), among others. Studies reported that stem cells could decrease proinflammatory cytokines (e.g., TNF-α, IFN-γ, IL-17) and fibrosis-related markers, while increasing levels of antiinflammatory cytokines (e.g., IL-10, IL-4) and regulatory immune cells such as Tregs (regulatory T cells). Stem cells could affect immune homeostasis via modulating in macrophage polarization, T cell subsets, and B cell activity, resulting in attenuated fibrotic progression and improved liver function.
Despite variability in cell types, routes of administration, and fibrosis models, the results support the potential of stem cell therapy to reform the hepatic immune microenvironment. However, more standardized protocols and clinical validations are required.
This study emphasizes the immunomodulatory potential of stem cells as a therapeutic method in liver fibrosis. It brings a clear view into their mechanisms of action and the foundation for future translational applications.
1. Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol. 2021;18(3):151-66.
2. Ghezelbash B, Shahrokhi N, Khaksari M, Ghaderi-Pakdel F, Asadikaram G. Hepatoprotective effects of Shilajit on high fat-diet induced non-alcoholic fatty liver disease (NAFLD) in rats. Horm Mol Biol Clin Investig. 2020;41(1).
3. Frozandeh F, Shahrokhi N, Khaksari M, Amiresmaili S, Asadikaram G, Shahrokhi N, et al. Evaluation of the protective effect of curcumin on encephalopathy caused by intrahepatic and extrahepatic damage in male rats. Iran J Basic Med Sci. 2021;24(6):760-6.
4. Khoramipour K, Rajizadeh MA, Akbari Z, Arjmand M. The effect of high-intensity interval training on type 2 diabetic muscle: A metabolomics-based study. Heliyon. 2024;10(15):e34917.
5. Henderson NC, Rieder F, Wynn TA. Fibrosis: from mechanisms to medicines. Nature. 2020;587(7835):555-66.
6. Gao CC, Bai J, Han H, Qin HY. The versatility of macrophage heterogeneity in liver fibrosis. Front Immunol. 2022;13:968879.
7. Zhang H, Chen Q, Dahan A, Xue J, Wei L, Tan W, et al. Transcriptomic analyses reveal the molecular mechanisms of schisandrin B alleviates CCl4-induced liver fibrosis in rats by RNA-sequencing. Chem Biol Interact. 2019;309:108675.
8. Liu Z, Zhu P, Zhang L, Xiong B, Tao J, Guan W, et al. Autophagy inhibition attenuates the induction of anti-inflammatory effect of catalpol in liver fibrosis. Biomed Pharmacother. 2018;103:1262-71.
9. Raj D, Sharma V, Upadhyaya A, Kumar N, Joshi R, Acharya V, et al. Swertia purpurascens Wall ethanolic extract mitigates hepatic fibrosis and restores hepatic hepcidin levels via inhibition of TGFβ/SMAD/NFκB signaling in rats. J Ethnopharmacol. 2022;284:114741.
10. Milito A, Brancaccio M, D’Argenio G, Castellano I. Natural sulfur-containing compounds: An alternative therapeutic strategy against liver fibrosis. Cells. 2019;8(11):1356.
11. Amiresmaili S, Shahrokhi N, Khaksari M, Asadikaram G, Aflatoonian MR, Shirazpour S, et al. The hepatoprotective mechanisms of 17β-estradiol after traumatic brain injury in male rats: Classical and non-classical estrogen receptors. Biomed Pharmacother. 2021;213:111987.
12. Balogh J, Victor D 3rd, Asham EH, Burroughs SG, Boktour M, Saharia A, et al. Hepatocellular carcinoma: a review. J Hepatocell Carcinoma. 2016:41-53.
13. Affo S, Yu LX, Schwabe RF. The role of cancer-associated fibroblasts and fibrosis in liver cancer. Annu Rev Pathol. 2017;12:153-86.
14. Cuesta AM, Palao N, Bragado P, Gutierrez-Uzquiza A, Herrera B, Sánchez A, et al. New and old key players in liver cancer. Int J Mol Sci. 2023;24(24):17152.
15. Amiresmaili S, Khaksari M, Shahrokhi N, Abolhassani M. Evolution of TLR4 role in mediating the hepatoprotective effects of estradiol after traumatic brain injury in male rats. Biochem Pharmacol. 2020;178:114044.
16. Triantafyllou E, Woollard KJ, McPhail MJ, Antoniades CG, Possamai LA. The role of monocytes and macrophages in acute and acute-on-chronic liver failure. Front Immunol. 2018;9:2948.
17. Cogliati B, Yashaswini CN, Wang S, Sia D, Friedman SL. Friend or foe? The elusive role of hepatic stellate cells in liver cancer. Nat Rev Gastroenterol Hepatol. 2023;20(10):647-61.
18. Amiresmaili S, Khaksari M, Shahrokhi N, Abolhassani M. Corrigendum to ‘Evolution of TLR4 role in mediating the hepatoprotective effects of estradiol after traumatic brain injury in male rats’. Biochem Pharmacol. 2024;220:115987.
19. Sánchez PS, Rigual MDM, Djouder N. Inflammatory and non-inflammatory mechanisms controlling cirrhosis development. Cancers (Basel). 2021;13(20):5045.
20. Zhan W, Liao X, Chen Z, Li L, Tian T, Li R. Leucine-rich repeats and immunoglobulin 1 (LRIG1) ameliorates liver fibrosis and hepatic stellate cell activation via inhibiting SphK1/S1P pathway. Iran J Allergy Asthma Immunol. 2020;19(4):397-408.
21. Mortoglou M, Giatra C, Sinakos E. Acute-on-chronic liver failure: Pathophysiology, prognosis, and management. World J Clin Cases. 2022;10(33):12105-22.
22. Singh A, Osna NA, Kharbanda KK. Treatment options for alcoholic and non-alcoholic fatty liver disease: A review. World J Gastroenterol. 2017;23(36):6549-70.
23. Marcellin P, Kutala BK. Liver diseases: A major, neglected global public health problem requiring urgent actions and large-scale screening. Liver Int. 2018;38 Suppl 1:2-6.
24. S. M. Investigating the possible protective effect of Brassica oleracea (red cabbage) extract on thioacetamide-induced hepatotoxicity in rats. Egypt J Chem. 2023;66(5):335-6.
25. Babaei F, Moafizad A, Darvishvand Z, Mirzababaei M, Hosseinzadeh H, Nassiri-Asl M. Review of the effects of vitexin in oxidative stress-related diseases. Food Sci Nutr. 2020;8(10):2569-80.
26. Abood WN, Bradley C, Alzubaidi MA, Duque-Guimarães DE, Al-Yaseen ZH, Hasan MM, et al. Ricinus communis L.-derived phytochemicals as potential immunomodulatory agents: A narrative review. Molecules. 2023;28(12):4796.
27. Ahmad R, Srivastava A, Maurya CK, Rajendran SM, Arya A. Phytomedicines against liver fibrosis: A review on their mode of action. Front Pharmacol. 2022;13:947110.
28. Eidi A, Moghadam JN, Mortazavi P, Rajabzadeh A, Tavangar SM. Hepatoprotective effects of Berberis vulgaris L. extract on CCl4-induced hepatic damage in rats. Iran J Pharm Res. 2014;13(3):891-8.
29. Wen Y, Lambrecht J, Ju C, Tacke F. Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities. Cell Mol Immunol. 2021;18(1):45-56.
30. Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA. Liver fibrosis and repair: Immune regulation of wound healing in a solid organ. Nat Rev Immunol. 2014;14(3):181-94.
31. Marcellin P, Kutala BK. Liver diseases: A major, neglected global public health problem requiring urgent actions and large-scale screening. Liver Int. 2018;38 Suppl 1:2-6.
32. Geng J, Sun X, Wang P, Zhang S, Wang X, Wu H, et al. Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity. Nat Immunol. 2015;16(11):1142-52.
33. Li H, You H, Fan X, Jia J. Hepatic macrophages in liver fibrosis: Pathogenesis and potential therapeutic targets. BMJ Open Gastroenterol. 2016;3(1):e000079.
34. Li S, He Y, Chen K, Sun J, Zhang L, He Y, et al. RvD1 alleviates hepatic fibrosis through stimulating quiescent HSC reversion via NF-κB-Smad3-TGF-β pathway. Cell Death Dis. 2019;10(4):1-15.
35. Saiman Y, Friedman SL. The role of chemokines in acute liver injury. Front Physiol. 2012;3:213.
36. Khurana A, Sayed N, Allawadhi P, Weiskirchen R. It takes two to tango: Fibrosis in liver as well as in heart. Cells. 2021;10(2):346.
37. Ahmad I, Khan M, Raza SS, Rauf A, Muhammad N, Khan H, et al. Hepatoprotective potential of carvacrol in rodent model of thioacetamide-induced liver fibrosis and in silico evaluation of its inhibitory potential against matrix metalloproteinase-2. Medicina (Kaunas). 2019;55(9):557.
38. Baeck C, Wei X, Bartneck M, Fech V, Heymann F, Gassler N, et al. Pharmacological inhibition of the chemokine C-C motif chemokine ligand 2 (monocyte chemoattractant protein 1) accelerates liver fibrosis regression by suppressing Ly-6Chi macrophage infiltration in mice. Hepatology. 2014;59(3):1060-72.
39. Seki E, De Minicis S, Inokuchi S, Taura K, Miyai K, van Rooijen N, et al. CCR2 promotes hepatic fibrosis in mice. Hepatology. 2009;50(1):185-97.
40. Pradere JP, Kluwe J, De Minicis S, Jiao JJ, Gwak GY, Dapito DH, et al. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology. 2013;58(4):1461-73.
41. Heymann F, Trautwein C, Tacke F. Monocytes and macrophages as cellular targets in liver fibrosis. Inflamm Allergy Drug Targets. 2009;8(4):307-18.
42. 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.
43. Hammam OA, Elkhafif N, Attia YM, Mansour MT, Elmazar MM, Abdelsalam RM, et al. Wharton’s jelly-derived mesenchymal stem cells combined with praziquantel as a potential therapy for Schistosoma mansoni-induced liver fibrosis in mice. Sci Rep. 2020;10(1):1-15.
44. Hou X, Yu F, Man S, Huang D, Gao Y, Liu M, et al. Vaccination with a 22.6 kDa tegumental protein significantly reduces worm burden and egg granuloma in Schistosoma japonicum-infected mice. Parasites Vectors. 2020;13:1-10.
45. Takehara T, Tatsumi T, Suzuki T, Rucker EB 3rd, Hennighausen L, Jinushi M, et al. Hepatocyte-specific disruption of Bcl-xL leads to continuous hepatocyte apoptosis and liver fibrotic responses. Gastroenterology. 2004;127(4):1189-97.
46. Lee YA, Wallace MC, Friedman SL. Pathobiology of liver fibrosis: A translational success story. Gut. 2015;64(5):830-41.
47. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115(2):209-18.
48. Schwabe RF, Tabas I, Pajvani UB. Mechanisms of fibrosis development in nonalcoholic steatohepatitis. Gastroenterology. 2020;158(7):1913-28.
49. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24(7):908-22.
50. Ramachandran P, Iredale JP. Macrophages: Central regulators of hepatic fibrogenesis and fibrosis resolution. J Hepatol. 2012;56(6):1417-19.
51. Zhang CY, Yuan WG, He P, Lei JH, Wang CX. Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets. World J Gastroenterol. 2016;22(48):10512-22.
52. Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA. Liver fibrosis and repair: Immune regulation of wound healing in a solid organ. Nat Rev Immunol. 2014;14(3):181-94.
53. Yang YM, Seki E. TNFα in liver fibrosis. Curr Pathobiol Rep. 2015;3(4):253-61.
54. Chen XM, Liu JX, Dong HQ, Ma S, Ma YM, Cheng Y, et al. TNF-α antagonist attenuates liver fibrosis by down-regulating inflammatory signaling in a rat model. World J Gastroenterol. 2018;24(44):4970-79.
55. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214(2):199-210.
56. Weiskirchen R, Weiskirchen S, Tacke F. Organ and tissue fibrosis: Molecular signals, cellular mechanisms and translational implications. Mol Aspects Med. 2019;65:2-15.
57. Mormone E, George J, Nieto N. Molecular pathogenesis of hepatic fibrosis and current therapeutic approaches. Chem
Biol Interact. 2011;193(3):225-31.
58. Shi JH, Line PD. Effect of liver regeneration on malignant hepatic tumors. World J Gastroenterol. 2014;20(41):15026-32.
59. Sun M, Kisseleva T. Reversibility of liver fibrosis. Clin Res Hepatol Gastroenterol. 2015;39 Suppl 1:S60-3.
60. Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017;14(7):397-411.
61. Cai X, Chen H, Zhu D, Ruan L, Wang J, Wang J, et al. Serum microRNAs serve as novel biomarkers for the diagnosis of hepatocellular carcinoma. Clin Lab. 2013;59(9-10):1063-72.
62. Higashi T, Friedman SL, Hoshida Y. Hepatic stellate cells as key target in liver fibrosis. Adv Drug Deliv Rev. 2017;121:27-42.
63. Nwosu ZC, Battello N, Rothley M, Pioronska W, Sitek B, Ebert MP, et al. Liver cancer cell lines distinctly mimic the metabolic gene expression pattern of the corresponding human tumours. J Exp Clin Cancer Res. 2018;37(1):211.
64. Keenan BP, Fong L, Kelley RK. Immunotherapy in hepatocellular carcinoma: The complex interface between inflammation, fibrosis, and the immune response. J Immunother Cancer. 2019;7(1):267.
65. Weber S, Auer J, Fottner C, Bitzer M, Dollinger M, Ignatova S, et al. PD-1 and PD-L1 checkpoint inhibition for advanced hepatocellular carcinoma: Case series and review of the literature. Front Oncol. 2020;10:581351.
66. Sahin IH, Akce M, Alese O, Shaib W, Lesinski GB, El-Rayes B, et al. Immune checkpoint inhibitors for hepatocellular carcinoma: Current limitations and future directions. Hepat Oncol. 2018;5(3):HEP08.
67. Wang X, He Q, Shen H, Xia A, Tian W, Yu W, et al. Immune checkpoint inhibitor-related adverse events in liver cancer: Current understanding and management. Front Immunol. 2022;13:981599.
2. Ghezelbash B, Shahrokhi N, Khaksari M, Ghaderi-Pakdel F, Asadikaram G. Hepatoprotective effects of Shilajit on high fat-diet induced non-alcoholic fatty liver disease (NAFLD) in rats. Horm Mol Biol Clin Investig. 2020;41(1).
3. Frozandeh F, Shahrokhi N, Khaksari M, Amiresmaili S, Asadikaram G, Shahrokhi N, et al. Evaluation of the protective effect of curcumin on encephalopathy caused by intrahepatic and extrahepatic damage in male rats. Iran J Basic Med Sci. 2021;24(6):760-6.
4. Khoramipour K, Rajizadeh MA, Akbari Z, Arjmand M. The effect of high-intensity interval training on type 2 diabetic muscle: A metabolomics-based study. Heliyon. 2024;10(15):e34917.
5. Henderson NC, Rieder F, Wynn TA. Fibrosis: from mechanisms to medicines. Nature. 2020;587(7835):555-66.
6. Gao CC, Bai J, Han H, Qin HY. The versatility of macrophage heterogeneity in liver fibrosis. Front Immunol. 2022;13:968879.
7. Zhang H, Chen Q, Dahan A, Xue J, Wei L, Tan W, et al. Transcriptomic analyses reveal the molecular mechanisms of schisandrin B alleviates CCl4-induced liver fibrosis in rats by RNA-sequencing. Chem Biol Interact. 2019;309:108675.
8. Liu Z, Zhu P, Zhang L, Xiong B, Tao J, Guan W, et al. Autophagy inhibition attenuates the induction of anti-inflammatory effect of catalpol in liver fibrosis. Biomed Pharmacother. 2018;103:1262-71.
9. Raj D, Sharma V, Upadhyaya A, Kumar N, Joshi R, Acharya V, et al. Swertia purpurascens Wall ethanolic extract mitigates hepatic fibrosis and restores hepatic hepcidin levels via inhibition of TGFβ/SMAD/NFκB signaling in rats. J Ethnopharmacol. 2022;284:114741.
10. Milito A, Brancaccio M, D’Argenio G, Castellano I. Natural sulfur-containing compounds: An alternative therapeutic strategy against liver fibrosis. Cells. 2019;8(11):1356.
11. Amiresmaili S, Shahrokhi N, Khaksari M, Asadikaram G, Aflatoonian MR, Shirazpour S, et al. The hepatoprotective mechanisms of 17β-estradiol after traumatic brain injury in male rats: Classical and non-classical estrogen receptors. Biomed Pharmacother. 2021;213:111987.
12. Balogh J, Victor D 3rd, Asham EH, Burroughs SG, Boktour M, Saharia A, et al. Hepatocellular carcinoma: a review. J Hepatocell Carcinoma. 2016:41-53.
13. Affo S, Yu LX, Schwabe RF. The role of cancer-associated fibroblasts and fibrosis in liver cancer. Annu Rev Pathol. 2017;12:153-86.
14. Cuesta AM, Palao N, Bragado P, Gutierrez-Uzquiza A, Herrera B, Sánchez A, et al. New and old key players in liver cancer. Int J Mol Sci. 2023;24(24):17152.
15. Amiresmaili S, Khaksari M, Shahrokhi N, Abolhassani M. Evolution of TLR4 role in mediating the hepatoprotective effects of estradiol after traumatic brain injury in male rats. Biochem Pharmacol. 2020;178:114044.
16. Triantafyllou E, Woollard KJ, McPhail MJ, Antoniades CG, Possamai LA. The role of monocytes and macrophages in acute and acute-on-chronic liver failure. Front Immunol. 2018;9:2948.
17. Cogliati B, Yashaswini CN, Wang S, Sia D, Friedman SL. Friend or foe? The elusive role of hepatic stellate cells in liver cancer. Nat Rev Gastroenterol Hepatol. 2023;20(10):647-61.
18. Amiresmaili S, Khaksari M, Shahrokhi N, Abolhassani M. Corrigendum to ‘Evolution of TLR4 role in mediating the hepatoprotective effects of estradiol after traumatic brain injury in male rats’. Biochem Pharmacol. 2024;220:115987.
19. Sánchez PS, Rigual MDM, Djouder N. Inflammatory and non-inflammatory mechanisms controlling cirrhosis development. Cancers (Basel). 2021;13(20):5045.
20. Zhan W, Liao X, Chen Z, Li L, Tian T, Li R. Leucine-rich repeats and immunoglobulin 1 (LRIG1) ameliorates liver fibrosis and hepatic stellate cell activation via inhibiting SphK1/S1P pathway. Iran J Allergy Asthma Immunol. 2020;19(4):397-408.
21. Mortoglou M, Giatra C, Sinakos E. Acute-on-chronic liver failure: Pathophysiology, prognosis, and management. World J Clin Cases. 2022;10(33):12105-22.
22. Singh A, Osna NA, Kharbanda KK. Treatment options for alcoholic and non-alcoholic fatty liver disease: A review. World J Gastroenterol. 2017;23(36):6549-70.
23. Marcellin P, Kutala BK. Liver diseases: A major, neglected global public health problem requiring urgent actions and large-scale screening. Liver Int. 2018;38 Suppl 1:2-6.
24. S. M. Investigating the possible protective effect of Brassica oleracea (red cabbage) extract on thioacetamide-induced hepatotoxicity in rats. Egypt J Chem. 2023;66(5):335-6.
25. Babaei F, Moafizad A, Darvishvand Z, Mirzababaei M, Hosseinzadeh H, Nassiri-Asl M. Review of the effects of vitexin in oxidative stress-related diseases. Food Sci Nutr. 2020;8(10):2569-80.
26. Abood WN, Bradley C, Alzubaidi MA, Duque-Guimarães DE, Al-Yaseen ZH, Hasan MM, et al. Ricinus communis L.-derived phytochemicals as potential immunomodulatory agents: A narrative review. Molecules. 2023;28(12):4796.
27. Ahmad R, Srivastava A, Maurya CK, Rajendran SM, Arya A. Phytomedicines against liver fibrosis: A review on their mode of action. Front Pharmacol. 2022;13:947110.
28. Eidi A, Moghadam JN, Mortazavi P, Rajabzadeh A, Tavangar SM. Hepatoprotective effects of Berberis vulgaris L. extract on CCl4-induced hepatic damage in rats. Iran J Pharm Res. 2014;13(3):891-8.
29. Wen Y, Lambrecht J, Ju C, Tacke F. Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities. Cell Mol Immunol. 2021;18(1):45-56.
30. Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA. Liver fibrosis and repair: Immune regulation of wound healing in a solid organ. Nat Rev Immunol. 2014;14(3):181-94.
31. Marcellin P, Kutala BK. Liver diseases: A major, neglected global public health problem requiring urgent actions and large-scale screening. Liver Int. 2018;38 Suppl 1:2-6.
32. Geng J, Sun X, Wang P, Zhang S, Wang X, Wu H, et al. Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity. Nat Immunol. 2015;16(11):1142-52.
33. Li H, You H, Fan X, Jia J. Hepatic macrophages in liver fibrosis: Pathogenesis and potential therapeutic targets. BMJ Open Gastroenterol. 2016;3(1):e000079.
34. Li S, He Y, Chen K, Sun J, Zhang L, He Y, et al. RvD1 alleviates hepatic fibrosis through stimulating quiescent HSC reversion via NF-κB-Smad3-TGF-β pathway. Cell Death Dis. 2019;10(4):1-15.
35. Saiman Y, Friedman SL. The role of chemokines in acute liver injury. Front Physiol. 2012;3:213.
36. Khurana A, Sayed N, Allawadhi P, Weiskirchen R. It takes two to tango: Fibrosis in liver as well as in heart. Cells. 2021;10(2):346.
37. Ahmad I, Khan M, Raza SS, Rauf A, Muhammad N, Khan H, et al. Hepatoprotective potential of carvacrol in rodent model of thioacetamide-induced liver fibrosis and in silico evaluation of its inhibitory potential against matrix metalloproteinase-2. Medicina (Kaunas). 2019;55(9):557.
38. Baeck C, Wei X, Bartneck M, Fech V, Heymann F, Gassler N, et al. Pharmacological inhibition of the chemokine C-C motif chemokine ligand 2 (monocyte chemoattractant protein 1) accelerates liver fibrosis regression by suppressing Ly-6Chi macrophage infiltration in mice. Hepatology. 2014;59(3):1060-72.
39. Seki E, De Minicis S, Inokuchi S, Taura K, Miyai K, van Rooijen N, et al. CCR2 promotes hepatic fibrosis in mice. Hepatology. 2009;50(1):185-97.
40. Pradere JP, Kluwe J, De Minicis S, Jiao JJ, Gwak GY, Dapito DH, et al. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology. 2013;58(4):1461-73.
41. Heymann F, Trautwein C, Tacke F. Monocytes and macrophages as cellular targets in liver fibrosis. Inflamm Allergy Drug Targets. 2009;8(4):307-18.
42. 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.
43. Hammam OA, Elkhafif N, Attia YM, Mansour MT, Elmazar MM, Abdelsalam RM, et al. Wharton’s jelly-derived mesenchymal stem cells combined with praziquantel as a potential therapy for Schistosoma mansoni-induced liver fibrosis in mice. Sci Rep. 2020;10(1):1-15.
44. Hou X, Yu F, Man S, Huang D, Gao Y, Liu M, et al. Vaccination with a 22.6 kDa tegumental protein significantly reduces worm burden and egg granuloma in Schistosoma japonicum-infected mice. Parasites Vectors. 2020;13:1-10.
45. Takehara T, Tatsumi T, Suzuki T, Rucker EB 3rd, Hennighausen L, Jinushi M, et al. Hepatocyte-specific disruption of Bcl-xL leads to continuous hepatocyte apoptosis and liver fibrotic responses. Gastroenterology. 2004;127(4):1189-97.
46. Lee YA, Wallace MC, Friedman SL. Pathobiology of liver fibrosis: A translational success story. Gut. 2015;64(5):830-41.
47. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115(2):209-18.
48. Schwabe RF, Tabas I, Pajvani UB. Mechanisms of fibrosis development in nonalcoholic steatohepatitis. Gastroenterology. 2020;158(7):1913-28.
49. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24(7):908-22.
50. Ramachandran P, Iredale JP. Macrophages: Central regulators of hepatic fibrogenesis and fibrosis resolution. J Hepatol. 2012;56(6):1417-19.
51. Zhang CY, Yuan WG, He P, Lei JH, Wang CX. Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets. World J Gastroenterol. 2016;22(48):10512-22.
52. Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA. Liver fibrosis and repair: Immune regulation of wound healing in a solid organ. Nat Rev Immunol. 2014;14(3):181-94.
53. Yang YM, Seki E. TNFα in liver fibrosis. Curr Pathobiol Rep. 2015;3(4):253-61.
54. Chen XM, Liu JX, Dong HQ, Ma S, Ma YM, Cheng Y, et al. TNF-α antagonist attenuates liver fibrosis by down-regulating inflammatory signaling in a rat model. World J Gastroenterol. 2018;24(44):4970-79.
55. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214(2):199-210.
56. Weiskirchen R, Weiskirchen S, Tacke F. Organ and tissue fibrosis: Molecular signals, cellular mechanisms and translational implications. Mol Aspects Med. 2019;65:2-15.
57. Mormone E, George J, Nieto N. Molecular pathogenesis of hepatic fibrosis and current therapeutic approaches. Chem
Biol Interact. 2011;193(3):225-31.
58. Shi JH, Line PD. Effect of liver regeneration on malignant hepatic tumors. World J Gastroenterol. 2014;20(41):15026-32.
59. Sun M, Kisseleva T. Reversibility of liver fibrosis. Clin Res Hepatol Gastroenterol. 2015;39 Suppl 1:S60-3.
60. Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017;14(7):397-411.
61. Cai X, Chen H, Zhu D, Ruan L, Wang J, Wang J, et al. Serum microRNAs serve as novel biomarkers for the diagnosis of hepatocellular carcinoma. Clin Lab. 2013;59(9-10):1063-72.
62. Higashi T, Friedman SL, Hoshida Y. Hepatic stellate cells as key target in liver fibrosis. Adv Drug Deliv Rev. 2017;121:27-42.
63. Nwosu ZC, Battello N, Rothley M, Pioronska W, Sitek B, Ebert MP, et al. Liver cancer cell lines distinctly mimic the metabolic gene expression pattern of the corresponding human tumours. J Exp Clin Cancer Res. 2018;37(1):211.
64. Keenan BP, Fong L, Kelley RK. Immunotherapy in hepatocellular carcinoma: The complex interface between inflammation, fibrosis, and the immune response. J Immunother Cancer. 2019;7(1):267.
65. Weber S, Auer J, Fottner C, Bitzer M, Dollinger M, Ignatova S, et al. PD-1 and PD-L1 checkpoint inhibition for advanced hepatocellular carcinoma: Case series and review of the literature. Front Oncol. 2020;10:581351.
66. Sahin IH, Akce M, Alese O, Shaib W, Lesinski GB, El-Rayes B, et al. Immune checkpoint inhibitors for hepatocellular carcinoma: Current limitations and future directions. Hepat Oncol. 2018;5(3):HEP08.
67. Wang X, He Q, Shen H, Xia A, Tian W, Yu W, et al. Immune checkpoint inhibitor-related adverse events in liver cancer: Current understanding and management. Front Immunol. 2022;13:981599.
| Files | ||
| Issue | Articles in Press | |
| Section | Review Article(s) | |
| Keywords | ||
| Cell therapy Immunomodulation Inflammation Liver fibrosis Mesenchymal stem cells | ||
| Rights and permissions | |
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Rahimi S, Derakhshani A, Alifarsangi A, Khoshnazar SM, Shahrokhi N, Shakeri MH. Immunomodulatory Effects of Stem Cell Therapy in Liver Fibrosis: A Systematic Review. Iran J Allergy Asthma Immunol. 2025;:1-16.
