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Review | Open Access

Precise cell therapy for liver fibrosis: Endothelial cell and macrophage therapy

Liping Deng1Bingjie Wu1Kaini LiangHongen LiaoYanan Du( )
Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, 10084, China

1 These authors contributed equally to this work.

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Abstract

Liver fibrosis is typically caused by chronic viral hepatitis and, more recently, fatty liver disease associated with obesity. There are currently no approved drugs for liver cirrhosis, and liver transplantation is limited by donor scarcity, thus driving the investigation of novel therapeutic strategies. The development of liver fibrosis presents with stage- and zone-dependent characteristics that manifest as distinct dynamic changes during vascularization and extracellular matrix (ECM) deposition. However, current cellular therapies do not consider the spatiotemporal variations of liver fibrosis without identifying the precise location and stage to administer the intervention to achieve optimal therapeutic effects. Herein, we focus on endothelial cell (EC) and macrophage therapy for liver fibrosis because of their important roles in regulating the spatiotemporal changes of vascularization and ECM deposition during liver fibrosis progression. Overall, this review summarizes the stage-dependent EC and macrophage therapy for liver fibrosis, elucidates their respective mechanisms, and exemplifies potential strategies to realize precise cell therapy by targeting specific liver zones.

References

[1]

Wang P, Koyama Y, Liu X, et al. Promising therapy candidates for liver fibrosis. Front Physiol 2016;7: 47.

[2]

Hansel MC, Gramignoli R, Skvorak KJ, et al. The history and use of human hepatocytes for the treatment of liver diseases: the first 100 patients. Curr Protoc Toxicol 2014;62: 14 12 1–23.

[3]

Gupta S. Hepatocyte transplantation. J Gastroenterol Hepatol 2002;17(Suppl 3): S287–93.

[4]

Karsdal MA, Daniels SJ, Nielsen SH, et al. Collagen biology and non-invasive biomarkers of liver fibrosis. Liver Int 2020;40(4): 736–50.

[5]

Jimenez Calvente C, Sehgal A, Popov Y, et al. Specific hepatic delivery of procollagen alpha1(Ⅰ) small interfering RNA in lipid-like nanoparticles resolves liver fibrosis. Hepatology 2015;62(4): 1285–97.

[6]

Vallet SD, Ricard-Blum S. Lysyl oxidases: from enzyme activity to extracellular matrix cross-links. Essays Biochem 2019;63(3): 349–64.

[7]

Elbjeirami WM, Yonter EO, Starcher BC, et al. Enhancing mechanical properties of tissue-engineered constructs via lysyl oxidase crosslinking activity. J Biomed Mater Res 2003;66(3): 513–21.

[8]

Barry-Hamilton V, Spangler R, Marshall D, et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med 2010;16(9): 1009–17.

[9]

Loomba R, Lawitz E, Mantry PS, et al. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology 2018; 67(2): 549–59.

[10]

Raghu G, Brown KK, Collard HR, et al. Efficacy of simtuzumab versus placebo in patients with idiopathic pulmonary fibrosis: a randomised, double-blind, controlled, phase 2 trial. Lancet Respir Med 2017;5(1): 22–32.

[11]

Dobie R, Wilson-Kanamori JR, Henderson BEP, et al. Single-cell transcriptomics uncovers zonation of function in the mesenchyme during liver fibrosis. Cell Rep 2019;29(7): 1832–1847 e8.

[12]

Sancho P, Mainez J, Crosas-Molist E, et al. NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development. PLoS One 2012;7(9): e45285.

[13]

Swiderska-Syn M, Syn WK, Xie G, et al. Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy. Gut 2014;63(8): 1333. U186.

[14]

Aoyama T, Paik YH, Watanabe S, et al. Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent. Hepatology 2012;56(6): 2316–27.

[15]

Carvalho SN, Lira DC, Oliveira GP, et al. Decreased collagen types Ⅰ and Ⅳ, laminin, CK-19 and alpha-SMA expression after bone marrow cell transplantation in rats with liver fibrosis. Histochem Cell Biol 2010;134(5): 493–502.

[16]

de Carvalho SN, Helal-Neto E, Caldas de Andrade D, et al. Bone marrow mononuclear cell transplantation increases metalloproteinase-9 and 13 and decreases tissue inhibitors of metalloproteinase-1 and 2 expression in the liver of cholestatic rats. Cells Tissues Organs 2013;198(2): 139–48.

[17]

de Carvalho SN, da Cunha Lira D, Costa Cortez EA, et al. Bone marrow cell transplantation is associated with fibrogenic cells apoptosis during hepatic regeneration in cholestatic rats. Biochem Cell Biol 2013;91(2): 88–94.

[18]

de Andrade DC, de Carvalho SN, Pinheiro D, et al. Bone marrow mononuclear cell transplantation improves mitochondrial bioenergetics in the liver of cholestatic rats. Exp Cell Res 2015;336(1): 15–22.

[19]

de Souza VCA, Pereira TA, Teixeira VW, et al. Bone marrow-derived monocyte infusion improves hepatic fibrosis by decreasing osteopontin, TGF-beta1, IL-13 and oxidative stress. World J Gastroenterol 2017;23(28): 5146–57.

[20]

Suh YG, Kim JK, Byun JS, et al. CD11b(+) Gr1(+) bone marrow cells ameliorate liver fibrosis by producing interleukin-10 in mice. Hepatology 2012;56(5): 1902–12.

[21]

Farouk S, Sabet S, Abu Zahra FA, et al. Bone marrow derived-mesenchymal stem cells downregulate IL17A dependent IL6/STAT3 signaling pathway in CCl4-induced rat liver fibrosis. PLoS One 2018;13(10): e0206130.

[22]

Duman DG, Zibandeh N, Ugurlu MU, et al. Mesenchymal stem cells suppress hepatic fibrosis accompanied by expanded intrahepatic natural killer cells in rat fibrosis model. Mol Biol Rep 2019;46(3): 2997–3008.

[23]

Luo XY, Meng XJ, Cao DC, et al. Transplantation of bone marrow mesenchymal stromal cells attenuates liver fibrosis in mice by regulating macrophage subtypes. Stem Cell Res Ther 2019;10(1): 16.

[24]

Rong X, Liu J, Yao X, et al. Human bone marrow mesenchymal stem cells-derived exosomes alleviate liver fibrosis through the Wnt/beta-catenin pathway. Stem Cell Res Ther 2019;10(1): 98.

[25]

Pinheiro D, Dias I, Ribeiro Silva K, et al. Mechanisms underlying cell therapy in liver fibrosis: an overview. Cells 2019;8(11).

[26]

Liu F, Liu ZD, Wu N, et al. Transplanted endothelial progenitor cells ameliorate carbon tetrachloride-induced liver cirrhosis in rats. Liver Transplant 2009;15(9): 1092–100.

[27]

Thomas JA, Pope C, Wojtacha D, et al. Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function. Hepatology 2011;53(6): 2003–15.

[28]

Lee RH, Pulin AA, Seo MJ, et al. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the antiinflammatory protein TSG-6. Cell Stem Cell 2009;5(1): 54–63.

[29]

Garcia-Tsao G, Friedman S, Iredale J, et al. Now there are many (stages) where before there was one: in search of a pathophysiological classification of cirrhosis. Hepatology 2010;51(4): 1445–9.

[30]

Liu L, You Z, Yu H, et al. Mechanotransduction-modulated fibrotic microniches reveal the contribution of angiogenesis in liver fibrosis. Nat Mater 2017;16(12): 1252–61.

[31]

Steinman JB, Salomao MA, Pajvani UB. Zonation in NASH - a key paradigm for understanding pathophysiology and clinical outcomes. Liver Int 2021;41(11): 2534–46.

[32]

Droin C, Kholtei JE, Bahar Halpern K, et al. Space-time logic of liver gene expression at sub-lobular scale. Nature Metabolism 2021;3(1): 43–58.

[33]

Ben-Moshe S, Itzkovitz S. Spatial heterogeneity in the mammalian liver. Nat Rev Gastroenterol Hepatol 2019;16(7): 395–410.

[34]

Jungermann K, Kietzmann T. Zonation of parenchymal and nonparenchymal metabolism in liver. Annu Rev Nutr 1996;16: 179–203.

[35]

Gebhardt R. Metabolic zonation of the liver: regulation and implications for liver function. Pharmacol Ther 1992;53(3): 275–354.

[36]

Gola A, Dorrington MG, Speranza E, et al. Commensal-driven immune zonation of the liver promotes host defence. Nature 2021;589(7840): 131–6.

[37]

Guilliams M, Bonnardel J, Haest B, et al. Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches. Cell 2022;185(2): 379–396. e38.

[38]

Augustin HG, Koh GY. Organotypic vasculature: from descriptive heterogeneity to functional pathophysiology. Science 2017;357(6353).

[39]

Rafii S, Butler JM, Ding BS. Angiocrine functions of organ-specific endothelial cells. Nature 2016;529(7586): 316–25.

[40]

MacParland SA, Liu JC, Ma XZ, et al. Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations. Nat Commun 2018;9(1): 4383.

[41]

Strauss O, Phillips A, Ruggiero K, et al. Immunofluorescence identifies distinct subsets of endothelial cells in the human liver. Sci Rep 2017;7.

[42]

Gage BK, Liu JC, Innes BT, et al. Generation of functional liver sinusoidal endothelial cells from human pluripotent stem-cell-derived venous angioblasts. Cell Stem Cell 2020;27(2): 254–269 e9.

[43]

Poisson J, Lemoinne S, Boulanger C, et al. Liver sinusoidal endothelial cells: physiology and role in liver diseases. J Hepatol 2017;66(1): 212–27.

[44]

Xie G, Wang L, Wang X, et al. Isolation of periportal, midlobular, and centrilobular rat liver sinusoidal endothelial cells enables study of zonated drug toxicity. Am J Physiol Gastrointest Liver Physiol 2010;299(5): G1204–10.

[45]

Koch PS, Lee KH, Goerdt S, et al. Angiodiversity and organotypic functions of sinusoidal endothelial cells. Angiogenesis 2021;24(2): 289–310.

[46]

Su T, Yang Y, Lai S, et al. Single-cell transcriptomics reveals zone-specific alterations of liver sinusoidal endothelial cells in cirrhosis. Cell Mol Gastroenterol Hepatol 2021; 11(4): 1139–61.

[47]

Lin Y, Dong MQ, Liu ZM, et al. A strategy of vascular-targeted therapy for liver fibrosis. Hepatology 2021;76(3): 660–75.

[48]

Terkelsen MK, Bendixen SM, Hansen D, et al. Transcriptional dynamics of hepatic sinusoid-associated cells after liver injury. Hepatology 2020;72(6): 2119–33.

[49]

Gracia-Sancho J, Caparrós E, Fernández-Iglesias A, et al. Role of liver sinusoidal endothelial cells in liver diseases. Nat Rev Gastroenterol Hepatol 2021;18(6): 411–31.

[50]

Kantari-Mimoun C, Castells M, Klose R, et al. Resolution of liver fibrosis requires myeloid cell-driven sinusoidal angiogenesis. Hepatology 2015;61(6): 2042–55.

[51]

Gabele E, Brenner DA, Rippe RA. Liver fibrosis: signals leading to the amplification of the fibrogenic hepatic stellate cell. Front Biosci 2003;8: d69–77.

[52]

Kisseleva T, Brenner DA. Hepatic stellate cells and the reversal of fibrosis. J Gastroenterol Hepatol 2006;21(Suppl 3): S84–7.

[53]

Duffield JS, Forbes SJ, Constandinou CM, et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 2005; 115(1): 56–65.

[54]

Ramachandran P, Dobie R, Wilson-Kanamori JR, et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 2019;575(7783): 512–8.

[55]

van der Heide D, Weiskirchen R, Bansal R. Therapeutic targeting of hepatic macrophages for the treatment of liver diseases. Front Immunol 2019;10: 2852.

[56]

Tacke F, Zimmermann HW. Macrophage heterogeneity in liver injury and fibrosis. J Hepatol 2014;60(5): 1090–6.

[57]

Schuppan D, Kim YO. Evolving therapies for liver fibrosis. J Clin Invest 2013; 123(5): 1887–901.

[58]

Elsherif SA, Alm AS. Role of macrophages in liver cirrhosis: fibrogenesis and resolution. Anat Cell Biol 2022;55(1): 14–9.

[59]

Karimian G, Mohammadi-Karakani A, Sotoudeh M, et al. Attenuation of hepatic fibrosis through captopril and enalapril in the livers of bile duct ligated rats. Biomed Pharmacother 2008;62(5): 312–6.

[60]

Thabut D, Shah V. Intrahepatic angiogenesis and sinusoidal remodeling in chronic liver disease: new targets for the treatment of portal hypertension? J Hepatol 2010; 53(5): 976–80.

[61]

Moroni F, Dwyer BJ, Graham C, et al. Safety profile of autologous macrophage therapy for liver cirrhosis. Nat Med 2019;25(10): 1560–5.

[62]

Cai J, Ito M, Nagata H, et al. Treatment of liver failure in rats with end-stage cirrhosis by transplantation of immortalized hepatocytes. Hepatology 2002;36(2): 386–94.

[63]

Keighron C, Lyons CJ, Creane M, et al. Recent advances in endothelial progenitor cells toward their use in clinical translation. Front Med (Lausanne) 2018;5: 354.

[64]

Lan L, Liu R, Qin LY, et al. Transplantation of bone marrow-derived endothelial progenitor cells and hepatocyte stem cells from liver fibrosis rats ameliorates liver fibrosis. World J Gastroenterol 2018;24(2): 237–47.

[65]

Nakamura T, Torimura T, Sakamoto M, et al. Significance and therapeutic potential of endothelial progenitor cell transplantation in a cirrhotic liver rat model. Gastroenterology 2007;133(1): 91–107 e1.

[66]

Sakamoto M, Nakamura T, Torimura T, et al. Transplantation of endothelial progenitor cells ameliorates vascular dysfunction and portal hypertension in carbon tetrachloride-induced rat liver cirrhotic model. J Gastroenterol Hepatol 2013;28(1): 168–78.

[67]

Nakamura T, Torimura T, Iwamoto H, et al. Prevention of liver fibrosis and liver reconstitution of DMN-treated rat liver by transplanted EPCs. Eur J Clin Invest 2012;42(7): 717–28.

[68]

D'Avola D, Fernández-Ruiz V, Carmona-Torre F, et al. Phase 1-2 pilot clinical trial in patients with decompensated liver cirrhosis treated with bone marrow-derived endothelial progenitor cells. Transl Res 2017;188: 80–91 e2.

[69]

Gage BK, Merlin S, Olgasi C, et al. Therapeutic correction of hemophilia A by transplantation of hPSC-derived liver sinusoidal endothelial cell progenitors. Cell Rep 2022;39(1): 110621.

[70]

Russo FP, Alison MR, Bigger BW, et al. The bone marrow functionally contributes to liver fibrosis. Gastroenterology 2006;130(6): 1807–21.

[71]

Ma PF, Gao CC, Yi J, et al. Cytotherapy with M1-polarized macrophages ameliorates liver fibrosis by modulating immune microenvironment in mice. J Hepatol 2017; 67(4): 770–9.

[72]

Haideri SS, McKinnon AC, Taylor AH, et al. Injection of embryonic stem cell derived macrophages ameliorates fibrosis in a murine model of liver injury. NPJ Regen Med 2017;2: 14.

[73]

Pouyanfard S, Meshgin N, Cruz LS, et al. Human induced pluripotent stem cellderived macrophages ameliorate liver fibrosis. Stem Cell 2021;39(12): 1701–17.

[74]

Xu M, Xu HH, Lin Y, et al. LECT2, a ligand for Tie1, plays a crucial role in liver fibrogenesis. Cell 2019;178(6): 1478–1492 e20.

[75]

Maeder ML, Gersbach CA. Genome-editing technologies for gene and cell therapy. Mol Ther 2016;24(3): 430–46.

[76]

Aghajanian H, Kimura T, Rurik JG, et al. Targeting cardiac fibrosis with engineered T cells. Nature 2019;573(7774): 430–3.

[77]

Higashi T, Friedman SL, Hoshida Y. Hepatic stellate cells as key target in liver fibrosis. Adv Drug Deliv Rev 2017;121: 27–42.

[78]

Wang ZY, Keogh A, Waldt A, et al. Single-cell and bulk transcriptomics of the liver reveals potential targets of NASH with fibrosis. Sci Rep 2021;11(1): 19396.

[79]

Zhang L, Tian L, Dai X, et al. Pluripotent stem cell-derived CAR-macrophage cells with antigen-dependent anti-cancer cell functions. J Hematol Oncol 2020;13(1): 153.

[80]

Chen Y, Yu Z, Tan X, et al. CAR-macrophage: a new immunotherapy candidate against solid tumors. Biomed Pharmacother 2021;139: 111605.

[81]

Qi C, Jin Y, Chen Y, et al. TGase-mediated cell membrane modification and targeted cell delivery to inflammatory endothelium. Biomaterials 2021;269: 120276.

[82]

Alam IS, Steinberg I, Vermesh O, et al. Emerging intraoperative imaging modalities to improve surgical precision. Mol Imag Biol 2018;20(5): 705–15.

[83]

Oliveira DA, Feitosa RQ, Correia MM. Segmentation of liver, its vessels and lesions from CT images for surgical planning. Biomed Eng Online 2011;10: 30.

[84]

Monfardini L, Orsi F, Caserta R, et al. Ultrasound and cone beam CT fusion for liver ablation: technical note. Int J Hyperther 2018;35(1): 500–4.

[85]

Mirka H, Duras P, Baxa J, et al. Contribution of computed tomographic angiography to pretreatment planning of radio-embolization of liver tumors. Anticancer Res 2018;38(7): 3825–9.

[86]

Nasser M, Wu Y, Danaoui Y, et al. Engineering microenvironments towards harnessing pro-angiogenic potential of mesenchymal stem cells. Mater Sci Eng C Mater Biol Appl 2019;102: 75–84.

[87]

Liu L, Zhang SX, Liao W, et al. Mechanoresponsive stem cells to target cancer metastases through biophysical cues. Sci Transl Med 2017;9(400).

[88]

Georges PC, Hui JJ, Gombos Z, et al. Increased stiffness of the rat liver precedes matrix deposition: implications forfibrosis. Am J Physiol Gastrointest Liver Physiol 2007;293(6): G1147–54.

[89]

Schweller RM, Wu ZJ, Klitzman B, et al. Stiffness of protease sensitive and cell adhesive PEG hydrogels promotes neovascularization in vivo. Ann Biomed Eng 2017;45(6): 1387–98.

[90]

Friedemann M, Kalbitzer L, Franz S, et al. Instructing human macrophage polarization by stiffness and glycosaminoglycan functionalization in 3D collagen networks. Adv Healthc Mater 2017;6(7).

iLIVER
Pages 265-274
Cite this article:
Deng L, Wu B, Liang K, et al. Precise cell therapy for liver fibrosis: Endothelial cell and macrophage therapy. iLIVER, 2022, 1(4): 265-274. https://doi.org/10.1016/j.iliver.2022.11.002

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Received: 08 September 2022
Revised: 30 October 2022
Accepted: 07 November 2022
Published: 19 November 2022
© 2022 The Authors. Published by Elsevier Ltd on behalf of Tsinghua University Press.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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