上皮-间充质转化对肝纤维化作用的研究进展

摘要/Abstract

摘要： 上皮-间充质转化在许多生理和病理过程中都具有重要作用,近年研究证明,肝纤维化过程中同样存在上皮-间充质转化现象。本文综合国内外研究成果,阐述发生上皮-间充质转化的肝源细胞(肝细胞、胆管上皮细胞、肝祖细胞、肝星状细胞)以及肝纤维化发生发展过程中上皮-间充质转化涉及的信号通路及调节机制,并探讨了以上皮-间充质转化为靶标的抗肝纤维治疗策略的可行性及研究进展。

关键词: 肝纤维化, 上皮-间充质转化, 肝上皮细胞, 肝星状细胞, 信号通路

Abstract: The epithelial-mesenchymal transition (EMT) plays important roles in many physiologic and pathological progresses. Recent researches showed that EMT involved in the liver fibrosis. In this review, we first describe the cells in the liver which undergo EMT, including hepatocytes, cholangiocytes, hepatic progenitors and hepatic stellate cells. Then, we systematically present the possible signal pathways and regulatory mechanisms of EMT in liver fibrosis. Finally, the feasibility of anti-fibrosis treatment targeting EMT is discussed as well.

Key words: Liver fibrosis, Epithelial-mesenchymal transition, Liver epithelial cells, Hepatic stellate cells, Signal pathway

中图分类号:

R965.2

成志云, 彭俊纯, 吕颖慧. 上皮-间充质转化对肝纤维化作用的研究进展[J]. 中国临床药理学与治疗学, 2013, 18(8): 928-936.

CHENG Zhi-yun, PENG Jun-chun, LV Ying-hui. Role of epithelial-mesenchymal transition in the liver fibrosis[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2013, 18(8): 928-936.

参考文献

[1] Greenburg G, Hay ED. Epithelia suspended in collagengels can lose polarity and express characteristics of migrating mesenchymal cells[J]. J Cell Biol, 1982, 95(1): 333-339.
[2] Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition[J]. J Clin Invest, 2009, 119(6): 1420-1428.
[3] Wendt MK, Allington TM, Schiemann WP. Mechanisms of the epithelial-mesenchymal transition by TGF-beta[J]. Future Oncol, 2009, 5(8):1145-1168.
[4] Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival: Implications in development and cancer[J]. Development, 2005, 132(14): 3151-3161.
[5] Gonzalez-Moreno O, Lecanda J, Green JE, et al. VEGF elicits epithelial-mesenchymal transition(EMT) in prostate intraepithelial neoplasia (PIN)-like cells via an autocrine loop[J]. Exp Cell Res, 2010, 316(14): 554-567.
[6] Cho HJ, Baek KE, Saika S, et al. Snail is required for transforming growth factor-beta induced epithelial-mesenchymal transition by activating PI3 kinase/ Aktsignal pathway[J]. Biochem Biophys Res Commun, 2007, 353(2): 337-343.
[7] Xu SY, Li J, Geng MY. The signal transduction and drug development of epithelial-mesenchymal transition[J]. Chin Pharmacol Bull, 2008, 24(9): 1131-1134.
[8] Kuroda N, Guo L, Miyazaki E, et al. The appearance of myofibroblasts and the disappearance of CD34-positive stromal cells in the area adjacent to xanthogranulomatous foci of chronic cholecystitis[J]. Histol Histopathol, 2005, 20(1): 127-133.
[9] Bose SK, Meyer K, Di Bisceglie AM, et al. Hepatitis C virus induces epithelial-mesenchymal transition in primary human hepatocytes[J]. J Virol, 2012, 86(24): 13621-13628.
[10] Shih HH, Sheen IJ, Su CW, et al. Hepatitis D virus isolates with low replication and epithelial- mesenchymal transition-inducing activity are associated with disease remission[J]. J Virol, 2012, 86 (17): 9044-9054.
[11] Copple BL. Hypoxia stimulates hepatocyte epithelial to mesenchymal transition by hypoxia-inducible factor and transforming growth factor-beta-dependent mechanisms[J]. Liver Int, 2010, 30(5): 669-682.
[12] Lopez-Novoa JM, Nieto MA. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression[J]. EMBO Mol Med, 2009, 1(6/7): 303-314.
[13] Díaz R, Kim JW, Hui JJ, et al. Evidence for the epithelial to mesenchymal transition in biliary atresia fibrosis[J]. Hum Pathol, 2008, 39(1): 102-115.
[14] Omenetti A, Porrello A, Jung Y, et al. Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans[J]. J Clin Invest, 2008, 118(10): 3331-3342.
[15] Harada K, Sato Y, Ikeda H,et al. Epithelial-mesenchymal transition induced by biliary innate immunity contributes to the sclerosing cholangiopathy of biliary atresia[J]. J Pathol, 2009, 217(5): 654-64.
[16] Syn WK, Jung Y, Omenetti A, et al. Hedgehog mediated epithelial to mesenchymal transition and fibrogenic repair in nonalcoholic fatty liver disease[J]. Gastroenterology, 2009, 137(4): 1478-1488.
[17] 周斌, 张培建. 胆管上皮细胞的生理及其与胆管疾病的相关性[J]. 中国普通外科杂志, 2007, 16(7): 681-683.
[18] Zeisberg M, Yang C, Martino M, et al. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition[J]. J Biol Chem, 2007, 282(32): 23337-23347.
[19] Harada K, Sato Y, Ikeda H, et al. Epithelial mesenchymal transition induced by biliary innate immunity contributes to the sclerosing cholangiopathy of biliary atresia[J]. J Pathol, 2009, 217(5): 654-664.
[20] Scholten D, Osterreicher CH, Scholten A, et al. Genetic labeling does not detect epithelial-to- mesenchymal transition of cholangiocytes in liver fibrosis in mice[J]. Gastroenterology, 2010, 139(3): 987-998.
[21] Kaimori A, Potter J, Kaimori JY, et al. Transforming growth factor-beta1 induces an epithelial-to- mesenchymal transition state in mouse hepatocytes in vitro[J]. J Biol Chem, 2007, 282(30): 22089-22101.
[22] Meindl-Beinker NM, Dooley S. Transforming growth factor-beta and hepatocyte transdifferentiation in liver fibrogenesis[J]. J Gastroenterol Hepatol, 2008, 23 (Suppl 1): S122-S127.
[23] Dooley S, Hamzavi J, Ciucian L, et al. Hepatocyte specific Smad7 expression attenuates TGF-beta- mediated fibrogenesis and protects against liver damage[J]. Gastroenterology, 2008, 135(2): 642-659.
[24] Nittta T, Kim JS, Mohuczy D, et al. Muring cirrhosis induces hepatocyte epithelial mesenchymal transition and laterations in survival signaling pathways[J]. Hepatology, 2008, 48(3): 909-919.
[25] 陈珺明, 季光. 肝脏祖细胞的表型特征及生物学功能[J]. 世界华人消化杂志, 2008, 16(22): 2482-2486.
[26] Sicklick JK, Choi SS, Bustamante M, et al. Evidence for epithelial-mesenchymal transitions in adult liver cells[J]. Am J Physiol Gastrointest Liver Physiol, 2006, 291(4): G575-G583.
[27] Ji S, Wang X, Shu J, et al. In vitro generation of myofi broblasts-like cells from liver epithelial progenitor cells of rhesus monkey (Macaca mulatta)[J]. In Vitro Cell Dev Biol Anim, 2011, 47(5-6): 383-390.
[28] Loo CK, Wu XJ. Origin of stellate cells from submesothelial cells in a developing human liver[J]. Liver Int, 2008, 28(10): 1437-1445.
[29] Asahina K, Tsai SY, Li P, et al. Mesenchymal origin of hepatic stellate cells, submseothelial cells, and perivascular mesenchymal cells during mouse liver development[J]. Hepatology, 2009, 49(3): 998-1011.
[30] Carmona R, Bonzalez-Iriarte M, Perez-Pomares JM, et al. Localization of the Wilm'stumour protein WT1 in avian embryos[J]. Cell Tissue Re, 2001, 303 (2): 173-186.
[31] Ijpenberg A, Perez-Pomares JM, Guadix JA, et al. Wt1 and retinoic acid signaling are essential for stellate cell development and liver morphogenesis[J]. Dev Biol, 2007, 312(1): 157-170.
[32] Kordes C, Sawitza I, Muller-Marbach A, et al. CD133+ hepatic stellate cells are progenitor cells[J]. Biochem Biophys Res Commun, 2007, 352(2): 410-417.
[33] Dong H, Wang HF, Gao YB, et al. Hepatic progenitor cell represents a transitioning cell population between liver epithelium and stroma[J]. Med Hypotheses, 2011, 76(6): 809-812.
[34] Yang L, Jung YM ,Omenetti A, et al. Fate-mapping evidence that hepatic stellate cells are epithelial progenitors in adult mouse livers[J]. Stem Cells, 2008, 26(8): 2104-2113.
[35] Shafiei MS, Rockey DC. The role of integrin-linked kinase in liver wound healing[J]. J Biol Chem, 2006, 281(34): 24863-24872.
[36] Zhang Y, Ikegami T, Honda A, et al. Involvement of integrin-linked kinase in carbon tetrachloride- induced hepatic fibrosis in rats[J]. Hepatology, 2006, 44(3): 612-622.
[37] Lim YS, Kim KA, Jung JO, et al. Modulation of cytokeratin expression during in vitro cultivation of human hepatic stellate cells: evidence of transdifferentiation from epithelial to mesenchymal phenotype[J]. Histochem Cell Biol, 2002, 118(2): 127-136.
[38] Lim YS, Lee HC, Lee HS. Switch of cadherin expression from E- to N-type during the activation of rat hepatic stellate cells[J]. Histochem Cell Biol, 2007, 127(2): 149-160.
[39] Itoh S, Itoh F, Goumans MJ, et al. Signaling of transforming growth factor-beta family members through Smad proteins[J]. Eur J Biochem, 2000, 267(24): 6954-6967.
[40] Miyazono K. Transforming growth factor-beta signaling in epithelial mesenchymal transition and progression of cancer[J]. Proc Jpn Acad Ser B Phys Biol Sci, 2009, 85(8): 314-323.
[41] Shi Y, Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus[J]. Cell, 2003, 113(6): 685-700.
[42] Massagué J, Seoane J, Wotton D. Smad transcription factors[J]. Genes Dev, 2005, 19(23): 2783-2810.
[43] Zhong W, Shen WF, Ning BF, et al. Inhibition of extracellular signal regulated kinase 1 by adenovirus mediated small interfering RNA attenuates hepatic fibrosis in rats[J]. Hepatology, 2009, 50(5): 1524-1536.
[44] Li J, Wang W, Huang X, et al. Advanced glycation end products induce tubular epithelia- myofibroblast transition through the RAGE-ERK1 /2MAP kinase signaling pathway[J]. Am J Pathol, 2004, 164(4): 1389-1397.
[45] Zeisberg M, Neilson EG. Biomarkers for epithelial msenchrmal transitions[J]. J Clin Invest, 2009, 119(6): 1429-1437.
[46] Aoyagi-Ikeda K, Maeno T, Matsui H, et al. Notch induces myofibroblast differentiation of alveolar epithelial cells via transforming growth factor-beta-Smad3 pathway[J]. Am J Respir Cell Mol Biol, 2011, 45(1): 136-144.
[47] Nyhan KC, Faherty N, Murray G, et al. Jagged/Notch signalling is required for a subset of TGF 1 responses in human kidney epithelial cells [J]. Biochim Biophys Acta, 2010, 1803(12): 1386-1395.
[48] Zhu F, Li T, Qiu F, et al. Preventive effect of Notch signaling inhibition by a gamma-secretase inhibitor on peritoneal dialysis fluid-induced peritoneal fibrosis in rats [J]. Am J Pathol, 2010, 176 (2):650-659.
[49] 张志波, 胡传兵, 高红, 等. 胆道闭锁患儿肝组织细胞因子及相关基因表达的研究[J]. 中华小儿外科杂志, 2008, 29(11): 667-670.
[50] Katoh Y, Katoh M. Hedgehog signaling, epithelial-to-mesenchymal transition and miRNA[J]. Int J Mol Med, 2008, 22(3): 271-275.
[51] Zhou Y, Jia X, Wang G, et al. PI-3K/AKT and ERK signaling pathways mediate leptin-induced inhibition of PPAR gamma gene expression in primary rat hepatic stellate cells[J]. Mol Cell Biochem, 2009, 325(1/2): 131-139.
[52] Godoy P, Hengstler JG, Ilkavets I, et al. Extracellular matrix modulates sensitivity of hepatocytes to fibroblastoid dedifferetiation and transforming growth factor beta-induced apoptosis[J]. Hepatology, 2009, 49(6): 2031-2043.
[53] Saika S, Ikeda K, Yamanaka O, et al. Adenoviral gene transfer of BMP-7, Id2, or Id3 suppresses injury- induced epithelial to mesenchymal transition of lens epithelium in mice[J]. Am J Physiol Cell Physiol, 2006, 290(1): C282- C289.
[54] Das S, Becker BN, Hoffmann FM, et al. Complete reversal of epithelial to mesenchymal transition requires inhibition of both ZEB expression and the Rho pathway[J]. BMC Cell Biol, 2009, 10: 94.
[55] Yang J, Dai C, Iiu Y. A novel mechanism by which hepatocyte growth factor blocks tubular epithelial to mesenchymal transition[J]. J Am Soc Nephrol, 2005, 16(1): 68-78.
[56] Zeisberg M, Hanai J, Sugimoto H, et a1. BMP-7 counteracts TGF-beta1 induced epithelial-to- mesenchymal transition and reverses chronic renal injury[J]. Nat Med, 2003, 9(7): 964-968.
[57] 白久旭, 韩敬明, 李旭, 等. Netrin-1慢病毒表达载体的构建及延缓TGF-β诱导HK-2细胞上皮-间充质转化的初步研究[J]. 现代生物医学进展, 2012, 12(27): 5234-5204.
[58] 梁瑞, 张继帅, 叶辉, 等. Rack1 敲低促进 TGF-β诱导的A549细胞的上皮-间充质转化[J]. 军事医学, 2012, 36(1): 27-30.
[59] 连耀国, 张颖娟, 郑法雷. VEGF 对上皮间充质转化的抑制与Smad信号途径及SnoN表达的变化[J]. 北京医学, 2012, 34(4): 299-304.
[60] 张颖娟, 连耀国, 李雪梅, 等. VEGF₁₆₅抑制HK2细胞上皮-间充质转化过程中NOTCH信号系统的变化[J]. 基础医学与临床, 2010, 30(10): 1029-1036.
[61] Dooley S, Hamzavi J, Ciuclan L, et al. Hepatocyte-specific Smad7 expression attenuates TGF-beta- mediated fibrogenesis and protects against liver damage[J]. Gastroenterology, 2008, 135(2): 642-659.
[62] Xia JL, Dai C, Michalopoulos GK, et al. Hepatocyte growth factor attenuates liver fibrosis induced by bile duct ligation[J]. Am J Pathol , 2006, 168(5): 1500-1512.
[63] Yue HY, Yin C, Hou JL, et al. Hepatocyte nuclear factor 4alpha attenuates hepatic fibrosis in rats[J]. Gut, 2010, 59(2): 236 -246.
[64] 马东红, 苏颖, 李明喜, 等. 地塞米松对马兜铃酸诱导的人肾小管上皮-间充质转化的作用及可能机制[J]. 北京医学, 2012, 34(4): 305-309.
[65] Fang LP, Lin Q, Tang CS, et al. Hydrogen sulfide attenuates epithelial-mesenchymal transition of human alveolar epithelial cells[J]. Pharmacol Res, 2010, 61(4): 298.
[66] Schwer CI, Stoll P, Goebel U, et al. Effects of hydrogen sulfide on rat pancreatic stellate cells[J]. Pancreas, 2012, 41(1): 74-83.
[67] Li Y, Wen X, Spataro BC, et al. Hepatocyte growth factor is a downstream effector that mediates the antifibrotic action of peroxisome proliferator-activated receptor-gamma agonists[J]. J Am Soc Nephrol, 2006, 17(1): 54-65.
[68] Hills CE, Willars GB, Brunskill NJ. Proinsulin C-peptide antagonizes the profibrotic effects of T-GFbeta1 via up-regulation of retinoic acid and HGF-related signaling pathways[J]. Mol Endocrinol, 2010, 24(4): 822-831.
[69] Wen X, Li Y, Hu K, et al. Hepatocyte growth factor receptor signaling mediates the anti-fibrotic action of 9-cis-retinoic acid in glomerular mesangial cells[J]. Am J Pathol, 2005, 167(4): 947-957.
[70] 黄彬, 姜傥, 皮蕾, 等. RNAi干扰WT1和Pax2 表达对逆转肾小管上皮间充质转化的作用[J]. 中山大学学报, 2011, 32(4): 442-448.
[71] Zhang J, Zhang H, Liu J, et al. miR-30 inhibits TGF-β₁-induced epithelial-to-mesenchymal transition in hepatocyte by targeting Snail1[J]. Biochem Biophys Res Commun, 2012, 417(3): 1100-1105.
[72] Liu Y. Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention[J]. J Am Soc Nephrol, 2004, 15(1): 11-12.
[73] 刘燕萍, 郑法雷, 刘建春. 低蛋白饮食加α-酮酸抑制CRF大鼠肾小管上皮间充质转化的作用及机制探讨[J]. 北京医学, 2011, 33(2): 100-105.
[74] 吴冀宁, 刘必成, 夏慧玲, 等. 虫草多糖对单侧输尿管梗阻小鼠肾小管上皮-间充质转化的影响[J]. 中国中西医结合肾病杂志, 2008, 9(5): 400-402.
[75] Benigni A, Zoja C, Corna D, et al. Add on anti-TGF-beta antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat [J]. Am Soc Nephrol , 2003, 14(7): 1816-1820.
[76] Schramek H, Feifel E, Marschitz I, et al. Loss of active MEK1-ERK1/2 restores epithelial phenotype and morphogenesis in transdifferentiated MDCK cells[J]. Am J Physiol Cell Physio1, 2003, 285(3): C652-C661.
[77] Yoshiji H, Noguchi R, Ikenaka Y, et al. Cocktail therapy with a combination of interferon, ribavirin and angiotensin-II type 1 receptor blocker attenuates murine liver fibrosis development [J]. Int J Mol Med, 2011, 28 (1): 81-88.