Nội dung được dịch bởi AI, chỉ mang tính chất tham khảo
Mô hình mạng tế bào và phân tích biểu hiện gen đơn bào tiết lộ các kiểu hình tế bào sao gan mới kiểm soát động lực tái sinh gan
Tóm tắt
Các kết quả gần đây từ các nghiên cứu về quy định gen và protein ở từng tế bào đang bắt đầu tiết lộ thực tế chưa được đánh giá đúng mức rằng các tế bào riêng lẻ trong một quần thể thể hiện sự biến đổi cao trong việc biểu hiện mRNA và protein (tức là, biến đổi phân tử). Bằng cách kết hợp mô hình hóa mạng tế bào và các phép đo biểu hiện gen quy mô cao ở từng tế bào, chúng tôi tìm cách hòa giải sự biến đổi phân tử cao trong các tế bào đơn bào với sự biến đổi tương đối thấp trong biểu hiện gen và protein ở quy mô mô và những phản ứng chức năng được điều phối cao của các mô đối phó với các thách thức sinh lý. Trong nghiên cứu này, chúng tôi tập trung vào việc liên quan các thay đổi động học trong phân phối các kiểu hình chức năng của tế bào sao gan (HSC) với phản ứng sinh lý được điều chỉnh chặt chẽ của sự tái sinh gan. Chúng tôi phát triển một mô hình toán học mô tả đóng góp của các quần thể kiểu hình chức năng của HSC vào sự tái sinh gan và kiểm tra các dự đoán của mô hình thông qua việc cách ly và phân loại phiên mã của từng HSC. Chúng tôi xác định và đặc trưng hóa bốn trạng thái phiên mã của HSC góp phần vào sự tái sinh gan, hai trong số đó được mô tả lần đầu tiên trong công trình này. Chúng tôi cho thấy rằng các quần thể trạng thái HSC thay đổi in vivo để đáp ứng với các thách thức cấp tính (trong trường hợp này, 70% cắt bỏ gan một phần) và các thách thức mãn tính (sử dụng ethanol mãn tính). Các kết quả của chúng tôi chỉ ra rằng HSC ảnh hưởng đến động lực của sự tái sinh gan thông qua việc điều chỉnh trạng thái mô trước khi xảy ra tổn thương cấp tính và thông qua việc kiểm soát động lực của sự cân bằng giữa các trạng thái tế bào. Hơn nữa, phương pháp mô hình hóa của chúng tôi cung cấp một khuôn khổ để hiểu cách mà sự cân bằng giữa các trạng thái tế bào ảnh hưởng đến động lực mô. Tổng hợp lại, các nghiên cứu mô hình hóa và thực nghiệm kết hợp của chúng tôi tiết lộ các trạng thái phiên mã HSC mới và chỉ ra rằng sự khác biệt cơ bản trong các kiểu hình HSC cũng như một sự cân bằng động của các chuyển tiếp giữa các kiểu hình này kiểm soát phản ứng tái sinh gan.
Từ khóa
#HSC #tái sinh gan #mô hình hóa mạng tế bào #biến đổi phân tử #trạng thái phiên mã.Tài liệu tham khảo
Tang F, Barbacioru C, Bao S, Lee C, Nordman E, Wang X, Lao K, Surani MA. Tracing the derivation of embryonic stem cells from the inner cell mass by single-cell RNA-Seq analysis. Cell Stem Cell. 2010;6(5):468–78.
Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, Cahill DP, Nahed BV, Curry WT, Martuza RL, Louis DN, Rozenblatt-Rosen O, Suva ML, Regev A, Bernstein BE. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014;344(6190):1396–401.
Amir ED, Davis KL, Tadmor MD, Simonds EF, Levine JH, Bendall SC, Shenfeld DK, Krishnaswamy S, Nolan GP, Pe'er D. viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia. Nat Biotechnol. 2013;31(6):545–52.
Treutlein B, Brownfield DG, Wu AR, Neff NF, Mantalas GL, Espinoza FH, Desai TJ, Krasnow MA, Quake SR. Reconstructing lineage hierarchies of the distal lung epithelium using single-cell RNA-seq. Nature. 2014;509(7500):371–5.
Spaethling JM, Sanchez-Alavez M, Lee J, Xia FC, Dueck H, Wang W, Fisher SA, Sul JY, Seale P, Kim J, Bartfai T, Eberwine J. Single-cell transcriptomics and functional target validation of brown adipocytes show their complex roles in metabolic homeostasis. FASEB J. 2016;30(1):81–92.
Dueck H, Khaladkar M, Kim TK, Spaethling JM, Francis C, Suresh S, Fisher SA, Seale P, Beck SG, Bartfai T. Deep sequencing reveals cell-type-specific patterns of single-cell transcriptome variation. Genome Biol. 2015;16(1):122.
Park J, Brureau A, Kernan K, Starks A, Gulati S, Ogunnaike B, Schwaber J, Vadigepalli R. Inputs drive cell phenotype variability. Genome Res. 2014;24(6):930–41.
Park J, Ogunnaike B, Schwaber J, Vadigepalli R. Identifying functional gene regulatory network phenotypes underlying single cell transcriptional variability. Prog Biophys Mol Biol. 2015;117(1):87–98.
Satija R, Farrell JA, Gennert D, Schier AF, Regev A. Spatial reconstruction of single-cell gene expression data. Nat Biotechnol. 2015;33(5):495–502.
Zeisel A, Munoz-Manchado AB, Codeluppi S, Lonnerberg P, La Manno G, Jureus A, Marques S, Munguba H, He L, Betsholtz C, Rolny C, Castelo-Branco G, Hjerling-Leffler J, Linnarsson S. Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science. 2015;347(6226):1138–42.
Bendall SC, Davis KL, Amir ED, Tadmor MD, Simonds EF, Chen TJ, Shenfeld DK, Nolan GP, Pe’er D. Single-cell trajectory detection uncovers progression and regulatory coordination in human B cell development. Cell. 2014;157(3):714–25.
Martinez-Jimenez CP, Odom DT. The mechanisms shaping the single-cell transcriptional landscape. Curr Opin Genet Dev. 2016;37:27–35.
Dueck H, Eberwine J, Kim J. Variation is function: are single cell differences functionally important? Bioessays. 2015;38(2):172–80.
Silberberg G, Bethge M, Markram H, Pawelzik K, Tsodyks M. Dynamics of population rate codes in ensembles of neocortical neurons. J Neurophysiol. 2004;91(2):704–9.
Paszek P, Ryan S, Ashall L, Sillitoe K, Harper CV, Spiller DG, Rand DA, White MR. Population robustness arising from cellular heterogeneity. Proc Natl Acad Sci U S A. 2010;107(25):11644–9.
Skene NG, Grant SG. Identification of vulnerable cell types in major brain disorders using single cell transcriptomes and expression weighted cell type enrichment. Front Neurosci. 2016;10:16.
Ringe B, Pichlmayr R, Wittekind C, Tusch G. Surgical treatment of hepatocellular carcinoma: experience with liver resection and transplantation in 198 patients. World J Surg. 1991;15(2):270–85.
Doci R, Gennari L, Bignami P, Montalto F, Morabito A, Bozzetti F. One hundred patients with hepatic metastases from colorectal cancer treated by resection: analysis of prognostic determinants. Br J Surg. 1991;78(7):797–801.
Tanemura A, Mizuno S, Wada H, Yamada T, Nobori T, Isaji S. Donor age affects liver regeneration during early period in the graft liver and late period in the remnant liver after living donor liver transplantation. World J Surg. 2012;36(5):1102–11.
Michalopoulos GK. Liver regeneration after partial hepatectomy critical analysis of mechanistic dilemmas. Am J Pathol. 2010;176(1):2–13.
Taub R. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol. 2004;5(10):836–47.
Fausto N. Liver regeneration. J Hepatol. 2000;32:19–31.
Cook D, Ogunnaike BA, Vadigepalli R. Systems analysis of non-parenchymal cell modulation of liver repair across multiple regeneration modes. BMC Syst Biol. 2015;9(1):1.
Malik R, Selden C, Hodgson H. The role of non-parenchymal cells in liver growth. Semin Cell Dev Biol. 2002;13(6):425–31.
Meijer C, Wiezer MJ, Diehl AM, Yang S, Schouten HJ, Meijer S, Rooijen N, Lambalgen AA, Dijkstra CD, Leeuwen PA. Kupffer cell depletion by CI2MDP-liposomes alters hepatic cytokine expression and delays liver regeneration after partial hepatectomy. Liver. 2000;20(1):66–77.
Rai RM, Yang SQ, McClain C, Karp CL, Klein AS, Diehl AM. Kupffer cell depletion by gadolinium chloride enhances liver regeneration after partial hepatectomy in rats. Am J Phys. 1996;270(6 Pt 1):G909–18.
DeLeve LD. Liver sinusoidal endothelial cells and liver regeneration. J Clin Invest. 2013;123(5):1861–6.
Ding B, Nolan DJ, Butler JM, James D, Babazadeh AO, Rosenwaks Z, Mittal V, Kobayashi H, Shido K, Lyden D. Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature. 2010;468(7321):310–5.
Hu J, Srivastava K, Wieland M, Runge A, Mogler C, Besemfelder E, Terhardt D, Vogel MJ, Cao L, Korn C, Bartels S, Thomas M, Augustin HG. Endothelial cell-derived angiopoietin-2 controls liver regeneration as a spatiotemporal rheostat. Science. 2014;343(6169):416–9.
Correnti JM, Cook D, Aksamitiene E, Swarup A, Ogunnaike B, Vadigepalli R, Hoek JB. Adiponectin fine-tuning of liver regeneration dynamics revealed through cellular network modelling. J Physiol Lond. 2015;593(2):365–83.
Kuttippurathu L, Patra B, Hoek JB, Vadigepalli R. A novel comparative pattern count analysis reveals a chronic ethanol-induced dynamic shift in immediate early NF-κB genome-wide promoter binding during liver regeneration. Mol BioSyst. 2016;12(3):1037–56.
Juskeviciute E, Dippold RP, Antony AN, Swarup A, Vadigepalli R, Hoek JB: Inhibition of miR-21 rescues liver regeneration after partial hepatectomy in ethanol-fed rats. Am J Physiol Gastrointest Liver Physiol 2016, :ajpgi00292.2016.
Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev. 2008;88(1):125–72.
Kisseleva T, Cong M, Paik Y, Scholten D, Jiang C, Benner C, Iwaisako K, Moore-Morris T, Scott B, Tsukamoto H, Evans SM, Dillmann W, Glass CK, Brenner DA. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc Natl Acad Sci U S A. 2012;109(24):9448–53.
Furchtgott LA, Chow CC, Periwal V. A model of liver regeneration. Biophys J. 2009;96(10):3926–35.
Tanoue S, Uto H, Kumamoto R, Arima S, Hashimoto S, Nasu Y, Takami Y, Moriuchi A, Sakiyama T, Oketani M, Ido A, Tsubouchi H. Liver regeneration after partial hepatectomy in rat is more impaired in a steatotic liver induced by dietary fructose compared to dietary fat. Biochem Biophys Res Commun. 2011;407(1):163–8.
Fausto N. Liver regeneration: from laboratory to clinic. Liver Transpl. 2001;7(10):835–44.
Yang S, Lin H, Yiu M, Albrecht J, Diehl A. Effects of chronic ethanol consumption on cytokine regulation of liver regeneration. Am J Physiol Gastrointest Liver Physiol. 1998;275(4):G696–704.
Tomiya T, Ogata I, Fujiwara K. Transforming growth factor α levels in liver and blood correlate better than hepatocyte growth factor with hepatocyte proliferation during liver regeneration. Am J Pathol. 1998;153(3):955–61.
Hayashi H, Sakai K, Baba H, Sakai T. Thrombospondin-1 is a novel negative regulator of liver regeneration after partial hepatectomy through transforming growth factor-beta1 activation in mice. Hepatology. 2012;55(5):1562–73.
Rudolph KL, Trautwein C, Kubicka S, Rakemann T, Bahr MJ, Sedlaczek N, Schuppan D, Manns MP. Differential regulation of extracellular matrix synthesis during liver regeneration after partial hepatectomy in rats. Hepatology. 1999;30(5):1159–66.
Marino S, Hogue IB, Ray CJ, Kirschner DE. A methodology for performing global uncertainty and sensitivity analysis in systems biology. J Theor Biol. 2008;254(1):178–96.
Jin X, Zimmers TA, Perez EA, Pierce RH, Zhang Z, Koniaris LG. Paradoxical effects of short-and long-term interleukin-6 exposure on liver injury and repair. Hepatology. 2006;43(3):474–84.
Li W, Liang X, Kellendonk C, Poli V, Taub R. STAT3 contributes to the mitogenic response of hepatocytes during liver regeneration. J Biol Chem. 2002;277(32):28411–7.
Qiu P, Gentles AJ, Plevritis SK. Discovering biological progression underlying microarray samples. PLoS Comput Biol. 2011;7(4):e1001123.
Huang DW, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4(1):44–57.
Yang SQ, Lin HZ, Yin M, Albrecht JH, Diehl AM. Effects of chronic ethanol consumption on cytokine regulation of liver regeneration. Am J Phys. 1998;275(4 Pt 1):G696–704.
Chen J, Bao H, Sawyer S, Kunos G, Gao B. Effects of short and long term ethanol on the activation of signal transducer and activator transcription factor 3 in normal and regenerating liver. Biochem Biophys Res Commun. 1997;239(3):666–9.
Horiguchi N, Ishac EJ, Gao B. Liver regeneration is suppressed in alcoholic cirrhosis: correlation with decreased STAT3 activation. Alcohol. 2007;41(4):271–80.
Israel Y, Khanna JM, Orrego H, Rachamin G, Wahid S, Britton R, Macdonald A, Kalant H. Studies on metabolic tolerance to alcohol, hepatomegaly and alcoholic liver disease. Drug Alcohol Depend. 1979;4(1):107–18.
Hendriks H, Verhoofstad W, Brouwer A, De Leeuw A, Knook D. Perisinusoidal fat-storing cells are the main vitamin a storage sites in rat liver. Exp Cell Res. 1985;160(1):138–49.
Paik Y, Schwabe RF, Bataller R, Russo MP, Jobin C, Brenner DA. Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology. 2003;37(5):1043–55.
Paik Y, Lee KS, Lee HJ, Yang KM, Lee SJ, Lee DK, Han K, Chon CY, Lee SI, Moon YM. Hepatic stellate cells primed with cytokines upregulate inflammation in response to peptidoglycan or lipoteichoic acid. Lab Investig. 2006;86(7):676–86.
Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115(2):209–18.
Maher JJ. Cell-specific expression of hepatocyte growth factor in liver. Upregulation in sinusoidal endothelial cells after carbon tetrachloride. J Clin Invest. 1993;91(5):2244–52.
Mullhaupt B, Feren A, Fodor E, Jones A. Liver expression of epidermal growth factor RNA. Rapid increases in immediate-early phase of liver regeneration. J Biol Chem. 1994;269(31):19667–70.
Engelmann JC, Amann T, Ott-Rötzer B, Nützel M, Reinders Y, Reinders J, Thasler WE, Kristl T, Teufel A, Huber CG. Causal modeling of Cancer-stromal communication identifies PAPPA as a novel stroma-secreted factor activating NFκB signaling in hepatocellular carcinoma. PLoS Comput Biol. 2015;11(5):e1004293.
Kaibori M, Kwon A, Nakagawa M, Wei T, Uetsuji S, Kamiyama Y, Okumura T, Kitamura N. Stimulation of liver regeneration and function after partial hepatectomy in cirrhotic rats by continuous infusion of recombinant human hepatocyte growth factor. J Hepatol. 1997;27(2):381–90.
Michalopoulos GK. Principles of liver regeneration and growth homeostasis. In: Comprehensive physiology; 2013.
Oe S, Lemmer ER, Conner EA, Factor VM, Levéen P, Larsson J, Karlsson S, Thorgeirsson SS. Intact signaling by transforming growth factor β is not required for termination of liver regeneration in mice. Hepatology. 2004;40(5):1098–105.
Genshaft AS, Li S, Gallant CJ, Darmanis S, Prakadan SM, Ziegler CG, Lundberg M, Fredriksson S, Hong J, Regev A. Multiplexed, targeted profiling of single-cell proteomes and transcriptomes in a single reaction. Genome Biol. 2016;17(1):188.
Guo G, Huss M, Tong GQ, Wang C, Sun LL, Clarke ND, Robson P. Resolution of cell fate decisions revealed by single-cell gene expression analysis from zygote to blastocyst. Dev Cell. 2010;18(4):675–85.
Poulin J, Tasic B, Hjerling-Leffler J, Trimarchi JM, Awatramani R. Disentangling neural cell diversity using single-cell transcriptomics. Nat Neurosci. 2016;19(9):1131–41.
Rizvi AH, Camara PG, Kandror EK, Roberts TJ, Schieren I, Maniatis T, Rabadan R. Single-cell topological RNA-seq analysis reveals insights into cellular differentiation and development. Nat Biotechnol. 2017;35(6):551–60.
Semrau S, Goldmann JE, Soumillon M, Mikkelsen TS, Jaenisch R, van Oudenaarden A. Dynamics of lineage commitment revealed by single-cell transcriptomics of differentiating embryonic stem cells. Nat Commun. 2017;8(1):1096.
Tasic B, Menon V, Nguyen TN, Kim TK, Jarsky T, Yao Z, Levi B, Gray LT, Sorensen SA, Dolbeare T. Adult mouse cortical cell taxonomy revealed by single cell transcriptomics. Nat Neurosci. 2016;19(2):335–46.
Tirosh I, Izar B, Prakadan SM, Wadsworth MH,2nd, Treacy D, Trombetta JJ, Rotem A, Rodman C, Lian C, Murphy G, Fallahi-Sichani M, Dutton-Regester K, Lin JR, Cohen O, Shah P, Lu D, Genshaft AS, Hughes TK, Ziegler CG, Kazer SW, Gaillard A, Kolb KE, Villani AC, Johannessen CM, Andreev AY, van Allen EM, Bertagnolli M, Sorger PK, Sullivan RJ, Flaherty KT, Frederick DT, Jane-Valbuena J, Yoon CH, Rozenblatt-Rosen O, Shalek AK, Regev A, Garraway LA: Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 2016, 352(6282):189–196.
Handel AE, Chintawar S, Lalic T, Whiteley E, Vowles J, Giustacchini A, Argoud K, Sopp P, Nakanishi M, Bowden R. Assessing similarity to primary tissue and cortical layer identity in induced pluripotent stem cell-derived cortical neurons through single-cell transcriptomics. Hum Mol Genet. 2016;25(5):989–1000.
Wang YJ, Schug J, Won KJ, Liu C, Naji A, Avrahami D, Golson ML, Kaestner KH. Single-cell transcriptomics of the human endocrine pancreas. Diabetes. 2016;65(10):3028–38.
Shekhar K, Lapan SW, Whitney IE, Tran NM, Macosko EZ, Kowalczyk M, Adiconis X, Levin JZ, Nemesh J, Goldman M: Comprehensive classification of retinal bipolar neurons by single-cell transcriptomics. Cell 2016, 166(5):1308–1323. e30.
Mederacke I, Dapito DH, Affò S, Uchinami H, Schwabe RF. High-yield and high-purity isolation of hepatic stellate cells from normal and fibrotic mouse livers. Nat Protoc. 2015;10(2):305–15.
Han L, Qiu P, Zeng Z, Jorgensen JL, Mak DH, Burks JK, Schober W, McQueen TJ, Cortes J, Tanner SD. Single-cell mass cytometry reveals intracellular survival/proliferative signaling in FLT3-ITD-mutated AML stem/progenitor cells. Cytometry Part A. 2015;87(4):346–56.
Yao Y, Liu R, Shin MS, Trentalange M, Allore H, Nassar A, Kang I, Pober JS, Montgomery RR. CyTOF supports efficient detection of immune cell subsets from small samples. J Immunol Methods. 2014;415:1–5.
Qiu P, Simonds EF, Bendall SC, Gibbs KD Jr, Bruggner RV, Linderman MD, Sachs K, Nolan GP, Plevritis SK. Extracting a cellular hierarchy from high-dimensional cytometry data with SPADE. Nat Biotechnol. 2011;29(10):886–91.
Yimlamai D, Christodoulou C, Galli GG, Yanger K, Pepe-Mooney B, Gurung B, Shrestha K, Cahan P, Stanger BZ, Camargo FD. Hippo pathway activity influences liver cell fate. Cell. 2014;157(6):1324–38.
Wang B, Zhao L, Fish M, Logan CY, Nusse R. Self-renewing diploid Axin2 cells fuel homeostatic renewal of the liver. Nature. 2015;524(7564):180–5.
Zhu GQ, Shi KQ, Huang S, Huang GQ, Lin YQ, Zhou ZR, Braddock M, Chen YP, Zheng MH. Network meta-analysis of randomized controlled trials: efficacy and safety of UDCA-based therapies in primary biliary cirrhosis. Medicine (Baltimore). 2015;94(11):e609.
Jain M, Patel N, Kamani P, Shah N, Kulkarni S, Gautam S, Shah A, Doshi S. Care of patients with liver cirrhosis: how are we doing? J Public Health Epidemiol. 2015;7(2):51–8.
Chiang DJ, Pritchard MT, Nagy LE. Obesity, diabetes mellitus, and liver fibrosis. Am J Physiol Gastrointest Liver Physiol. 2011;300(5):G697–702.
Higgins GM, Anderson RM. Experimental pathology of the liver I restoration of the liver of the white rat following partial surgical removal. Arch Pathol. 1931;12(2):186–202.
Juskeviciute E, Vadigepalli R, Hoek JB. Temporal and functional profile of the transcriptional regulatory network in the early regenerative response to partial hepatectomy in the rat. BMC Genomics. 2008;9:527.
Ye J, Coulouris G, Zaretskaya I, Cutcutache I, Rozen S, Madden TL: Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction. BMC Bioinformatics 2012, 13:134–2105-13-134.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods. 2001;25(4):402–8.
Venables WN, Ripley BD. Modern applied statistics with S. 4th ed. New York: Springer; 2002.
Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, Ellis B, Gautier L, Ge Y, Gentry J, Hornik K, Hothorn T, Huber W, Iacus S, Irizarry R, Leisch F, Li C, Maechler M, Rossini AJ, Sawitzki G, Smith C, Smyth G, Tierney L, Yang JY, Zhang J. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 2004;5(10):R80.
R Core Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2013. http://www.R-project.org/.
Oksanen J, Blanchet F, Kindt R, Legendre P, O'Hara R, Simpson G, Solymos P, Stevens M, Wagner H: vegan: community ecology package. R package 2013, version 2.0–10.
Bissell DM, Wang SS, Jarnagin WR, Roll FJ. Cell-specific expression of transforming growth factor-beta in rat liver. Evidence for autocrine regulation of hepatocyte proliferation. J Clin Invest. 1995;96(1):447–55.
Young LH, Periwal V. Metabolic scaling predicts post-hepatectomy liver regeneration after accounting for hepatocyte hypertrophy. Liver Transpl. 2015;22(4):476–84.
Liu Y, Ma Z, Zhao C, Wang Y, Wu G, Xiao J, McClain CJ, Li X, Feng W. HIF-1α and HIF-2α are critically involved in hypoxia-induced lipid accumulation in hepatocytes through reducing PGC-1α-mediated fatty acid β-oxidation. Toxicol Lett. 2014;226(2):117–23.
Maeno H, Ono T, Dhar DK, Sato T, Yamanoi A, Nagasue N. Expression of hypoxia inducible factor-1α during liver regeneration induced by partial hepatectomy in rats. Liver Int. 2005;25(5):1002–9.
Copple BL, Bustamante JJ, Welch TP, Kim ND, Moon J. Hypoxia-inducible factor-dependent production of profibrotic mediators by hypoxic hepatocytes. Liver Int. 2009;29(7):1010–21.
Barnes MA, McMullen MR, Roychowdhury S, Madhun NZ, Niese K, Olman MA, Stavitsky AB, Bucala R, Nagy LE. Macrophage migration inhibitory factor is required for recruitment of scar-associated macrophages during liver fibrosis. J Leukoc Biol. 2015;97(1):161–9.
Wang M, You Q, Lor K, Chen F, Gao B, Ju C. Chronic alcohol ingestion modulates hepatic macrophage populations and functions in mice. J Leukoc Biol. 2014;96(4):657–65.
Sica A, Invernizzi P, Mantovani A. Macrophage plasticity and polarization in liver homeostasis and pathology. Hepatology. 2014;59(5):2034–42.
Melgar-Lesmes P, Edelman ER. Monocyte-endothelial cell interactions in the regulation of vascular sprouting and liver regeneration in mouse. J Hepatol. 2015;63(4):917–25.
Chen G, Goeddel DV. TNF-R1 signaling: a beautiful pathway. Science. 2002;296(5573):1634–5.
Aggarwal BB. Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol. 2003;3(9):745–56.
Xing Z, Tremblay GM, Sime PJ, Gauldie J. Overexpression of granulocyte-macrophage colony-stimulating factor induces pulmonary granulation tissue formation and fibrosis by induction of transforming growth factor-beta 1 and myofibroblast accumulation. Am J Pathol. 1997;150(1):59–66.
Bozinovski S, Jones JE, Vlahos R, Hamilton JA, Anderson GP. Granulocyte/macrophage-colony-stimulating factor (GM-CSF) regulates lung innate immunity to lipopolysaccharide through Akt/Erk activation of NFkappa B and AP-1 in vivo. J Biol Chem. 2002;277(45):42808–14.
Ogawa D, Stone JF, Takata Y, Blaschke F, Chu VH, Towler DA, Law RE, Hsueh WA, Bruemmer D. Liver x receptor agonists inhibit cytokine-induced osteopontin expression in macrophages through interference with activator protein-1 signaling pathways. Circ Res. 2005;96(7):e59–67.
Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O'Garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol. 1991;147(11):3815–22.
de Waal Malefyt R, Abrams J, Bennett B, Figdor CG, de Vries JE. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991;174(5):1209–20.
Yang ZF, Poon RT, Luo Y, Cheung CK, Ho DW, Lo CM, Fan ST. Up-regulation of vascular endothelial growth factor (VEGF) in small-for-size liver grafts enhances macrophage activities through VEGF receptor 2-dependent pathway. J Immunol. 2004;173(4):2507–15.
Reeves HL, Friedman SL. Activation of hepatic stellate cells-a key issue in liver fibrosis. Front Biosci. 2002;7(4):808–26.
Li D, Friedman S. Liver fibrogenesis and the role of hepatic stellate cells: new insights and prospects for therapy. J Gastroenterol Hepatol. 1999;14(7):618–33.
De Minicis S, Seki E, Uchinami H, Kluwe J, Zhang Y, Brenner DA, Schwabe RF. Gene expression profiles during hepatic stellate cell activation in culture and in vivo. Gastroenterology. 2007;132(5):1937–46.
Jiang F, Parsons CJ, Stefanovic B. Gene expression profile of quiescent and activated rat hepatic stellate cells implicates Wnt signaling pathway in activation. J Hepatol. 2006;45(3):401–9.
Sakaida I, Hironaka K, Terai S, Okita K. Gadolinium chloride reverses dimethylnitrosamine (DMN)-induced rat liver fibrosis with increased matrix metalloproteinases (MMPs) of Kupffer cells. Life Sci. 2003;72(8):943–59.
Xu L, Hui AY, Albanis E, Arthur MJ, O'Byrne SM, Blaner WS, Mukherjee P, Friedman SL, Eng FJ. Human hepatic stellate cell lines, LX-1 and LX-2: new tools for analysis of hepatic fibrosis. Gut. 2005;54(1):142–51.
Wang H, Keiser JA. Hepatocyte growth factor enhances MMP activity in human endothelial cells. Biochem Biophys Res Commun. 2000;272(3):900–5.
Haruyama T, Ajioka I, Akaike T, Watanabe Y. Regulation and significance of hepatocyte-derived matrix metalloproteinases in liver remodeling. Biochem Biophys Res Commun. 2000;272(3):681–6.