Modeling Liver Fibrosis Using hiPSC-Derived Liver Organoids: Methods and Applications
DOI:
https://doi.org/10.62146/ijecbe.v3i1.117Keywords:
Antifibrotic, Disease Modeling, Hepatic Fibrosis, Human iPSCs, Liver OrganoidsAbstract
Liver fibrosis is a pathological state marked by the excessive buildup of extracellular matrix due to persistent liver damage. Despite the potential of traditional medicines, including antiviral medications and lifestyle adjustments, to decelerate fibrosis progression, a completely effective treatment is still lacking. This article examines the function of human-induced pluripotent stem cells (hiPSCs) in mimicking liver fibrosis. HiPSCs can differentiate into multiple liver cell types, such as hepatocytes, hepatic stellate cells, and endothelial cells, facilitating the reconstruction of liver microarchitecture in both two-dimensional cultures and three-dimensional organoids. These technologies offer critical insights into the pathophysiological underpinnings of the disease, facilitate the discovery of therapeutic targets, and aid in the development of innovative antifibrotic drugs. The use of hiPSCs not only enables novel methods for disease modeling but also presents intriguing opportunities for more targeted and effective regenerative therapy for liver fibrosis.
References
Berasain C, Arechederra M, Argemí J, Fernández-Barrena MG, Avila MA. Loss of liver function in chronic liver disease: An identity crisis. J Hepatol. 2023 Feb 1;78(2):401–14.
Engelmann C, Clària J, Szabo G, Bosch J, Bernardi M. Pathophysiology of decompensated cirrhosis: Portal hypertension, circulatory dysfunction, inflammation, metabolism and mitochondrial dysfunction. J Hepatol. 2021 Jul 1;75:S49–66.
Devarbhavi H, Asrani SK, Arab JP, Nartey YA, Pose E, Kamath PS. Global burden of liver disease: 2023 update. J Hepatol. 2023 Aug 1;79(2):516–37.
Wang C, Ma C, Gong L, Guo Y, Fu K, Zhang Y, et al. Macrophage Polarization and Its Role in Liver Disease. Front Immunol [Internet]. 2021 Dec 14 [cited 2025 Mar 3];12. Available from: https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.803037/full
Roehlen N, Crouchet E, Baumert T. Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives. Cells [Internet]. 2020 Apr 1;9. Available from: https://consensus.app/papers/liver-fibrosis-mechanistic-concepts-and-therapeutic-roehlen-crouchet/5d89bfe165e45c9a9cac6df950308ff2/
Tan Z, Sun H, Xue T, Gan C, Liu H, Xie Y, et al. Liver Fibrosis: Therapeutic Targets and Advances in Drug Therapy. Front Cell Dev Biol [Internet]. 2021 Sep 21;9. Available from: https://consensus.app/papers/liver-fibrosis-therapeutic-targets-and-advances-in-drug-tan-sun/f01f3d31a031525facc39bd7a69dab6c/
Ginès P, Krag A, Abraldes J, Solà E, Fabrellas N, Kamath P. Liver cirrhosis. The Lancet. 2021 Sep 17;398:1359–76.
Zamani M, Alizadeh-Tabari S, Ajmera V, Singh S, Murad MH, Loomba R. Global Prevalence of Advanced Liver Fibrosis and Cirrhosis in the General Population: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol [Internet]. 2024 Aug 27 [cited 2025 Mar 3];0(0). Available from: https://www.cghjournal.org/article/S1542-3565(24)00790-0/abstract
Nah E, Cho S, Kim S, Chu J, Kwon E, Cho HI. Prevalence of liver fibrosis and associated risk factors in the Korean general population: a retrospective cross-sectional study. BMJ Open [Internet]. 2021 Mar 1;11. Available from: https://consensus.app/papers/prevalence-of-liver-fibrosis-and-associated-risk-factors-nah-cho/75246c1b13d55949a83704e9344c2b1c/
Tapper EB. Use of Angiotensin-Converting Enzyme Inhibitors in Patients With Liver Disease. Gastroenterol Hepatol. 2023 Jan;19(1):65–7.
Hartley C, Van T, Karnsakul W. Direct-Acting Antiviral Agents in Prevention of Maternal–Fetal Transmission of Hepatitis C Virus in Pregnancy. Pathogens. 2024 Jun;13(6):508.
Rajapaksha I. Liver Fibrosis, Liver Cancer, and Advances in Therapeutic Approaches. Livers. 2022 Dec;2(4):372–86.
Li J, Tuo B. Current and Emerging Approaches for Hepatic Fibrosis Treatment. Gastroenterol Res Pract. 2021;2021(1):6612892.
Odagiri N, Matsubara T, Sato-Matsubara M, Fujii H, Enomoto M, Kawada N. Anti-fibrotic treatments for chronic liver diseases: The present and the future. Clin Mol Hepatol. 2020 Dec 3;27(3):413–24.
Garreta E, Kamm RD, Chuva de Sousa Lopes SM, Lancaster MA, Weiss R, Trepat X, et al. Rethinking organoid technology through bioengineering. Nat Mater. 2021 Feb;20(2):145–55.
Sampaziotis F, de Brito MC, Madrigal P, Bertero A, Saeb-Parsy K, Soares FAC, et al. Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation. Nat Biotechnol. 2015 Aug;33(8):845–52.
Kamiya A, Anzai K, Tsuruya K, Chikada H. Culture System of Bile Duct-Like Cystic Structures Derived from Human-Inducible Pluripotent Stem Cells. In: Tanimizu N, editor. Hepatic Stem Cells : Methods and Protocols [Internet]. New York, NY: Springer; 2019 [cited 2025 Mar 3]. p. 143–53. Available from: https://doi.org/10.1007/978-1-4939-8961-4_13
Bian W, Chen W, Nguyen T, Zhou Y, Zhang J. miR-199a Overexpression Enhances the Potency of Human Induced-Pluripotent Stem-Cell–Derived Cardiomyocytes for Myocardial Repair. Front Pharmacol [Internet]. 2021 Jun 3 [cited 2025 Mar 3];12. Available from: https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.673621/full
Alvarez-Palomo B, Sanchez-Lopez LI, Moodley Y, Edel MJ, Serrano-Mollar A. Induced pluripotent stem cell-derived lung alveolar epithelial type II cells reduce damage in bleomycin-induced lung fibrosis. Stem Cell Res Ther. 2020 Jun 3;11(1):213.
Ogawa S, Surapisitchat J, Virtanen C, Ogawa M, Niapour M, Sugamori KS, et al. Three-dimensional culture and cAMP signaling promote the maturation of human pluripotent stem cell-derived hepatocytes. Development. 2013 Aug 1;140(15):3285–96.
Coll M, Perea L, Boon R, Leite S, Vallverdú J, Mannaerts I, et al. Generation of Hepatic Stellate Cells from Human Pluripotent Stem Cells Enables In Vitro Modeling of Liver Fibrosis. Cell Stem Cell. 2018 Jul 1;23 1:101–13.
Tian C, Li L, Fan L, Brown A, Norris EJ, Morrison M, et al. A hepatoprotective role of peritumoral non-parenchymal cells in early liver tumorigenesis. Dis Model Mech [Internet]. 2023 Mar 1 [cited 2025 Mar 3];16(3). Available from: https://dx.doi.org/10.1242/dmm.049750
Wang D, He H, Wei C. Cellular and potential molecular mechanisms underlying transovarial transmission of the obligate symbiont Sulcia in cicadas. Environ Microbiol. 2023 Apr;25(4):836–52.
Liu J, Du Y, Xiao X, Tan D, He Y, Qin L. Construction of in vitro liver-on-a-chip models and application progress. Biomed Eng OnLine. 2024 Mar 15;23(1):33.
Bell CC, Chouhan B, Andersson LC, Andersson H, Dear JW, Williams DP, et al. Functionality of primary hepatic non-parenchymal cells in a 3D spheroid model and contribution to acetaminophen hepatotoxicity. Arch Toxicol. 2020 Apr 1;94(4):1251–63.
Macparland S, Liu J, Xuezhong, Innes B, Bartczak A, Gage B, et al. Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations. Nat Commun [Internet]. 2018 Oct 22;9. Available from: https://consensus.app/papers/single-cell-rna-sequencing-of-human-liver-reveals-distinct-macparland-liu/5f648a118d49579f94e6301709937cc1/
Ebrahimkhani MR, Neiman JAS, Raredon MSB, Hughes DJ, Griffith LG. Bioreactor technologies to support liver function in vitro. Adv Drug Deliv Rev. 2014 Apr 20;69–70:132–57.
Pandey E, Nour AS, Harris EN. Prominent Receptors of Liver Sinusoidal Endothelial Cells in Liver Homeostasis and Disease. Front Physiol [Internet]. 2020 Jul 21 [cited 2025 Mar 3];11. Available from: https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2020.00873/full
Kulle A, Thanabalasuriar A, Cohen TS, Szydlowska M. Resident macrophages of the lung and liver: The guardians of our tissues. Front Immunol [Internet]. 2022 Nov 30 [cited 2025 Mar 3];13. Available from: https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1029085/full
Friedman SL. Mechanisms of Hepatic Fibrogenesis. Gastroenterology. 2008 May 1;134(6):1655–69.
Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005 Feb 1;115(2):209–18.
Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol. 2021 Mar;18(3):151–66.
Tacke F, Zimmermann HW. Macrophage heterogeneity in liver injury and fibrosis. J Hepatol. 2014 May 1;60(5):1090–6.
DeLeve LD. Liver sinusoidal endothelial cells in hepatic fibrosis. Hepatology. 2015 May;61(5):1740.
Weiskirchen R, Tacke F. Cellular and molecular functions of hepatic stellate cells in inflammatory responses and liver immunology. Hepatobiliary Surg Nutr. 2014 Dec;3(6):34463–34363.
Heymann F, Tacke F. Immunology in the liver — from homeostasis to disease. Nat Rev Gastroenterol Hepatol. 2016 Feb;13(2):88–110.
Wells RG. The role of matrix stiffness in regulating cell behavior†. Hepatology. 2008 Apr;47(4):1394.
Kodariah L, Wahid AA. Pengaruh Ekstrak Biji Ketumbar (Coriandrum Sativum) Terhadap Kadar Trigliserida Dan Gambaran Histologi Hati Tikus (Rattus Novergicus) Yang Diinduksi Oleh Pakan Tinggi Lemak. J Biotek Medisiana Indones. 2020;9(1):47–54.
Lestari A, Tyas TAW. Profil Pemeriksaan Hematologi dan Fungsi Hati pada Lansia dengan Sirosis Hepatis. Muhammadiyah J Geriatr. 2023 Sep 21;4(1):65–72.
Kusuma MDS, Wulandari IAP. Perilaku Hidup Bersih dan Sehat untuk Pencegahan Penyakit Hepatitis di Panti Asuhan. J Kreat Pengabdi Kpd Masy PKM. 2024 Apr 1;7(4):1856–66.
Han HS, Kang G, Kim JS, Choi BH, Koo SH. Regulation of glucose metabolism from a liver-centric perspective. Exp Mol Med. 2016 Mar;48(3):e218–e218.
Hou Y, Hu S, Li X, He W, Wu G. Amino Acid Metabolism in the Liver: Nutritional and Physiological Significance. In: Wu G, editor. Amino Acids in Nutrition and Health: Amino acids in systems function and health [Internet]. Cham: Springer International Publishing; 2020 [cited 2025 Mar 3]. p. 21–37. Available from: https://doi.org/10.1007/978-3-030-45328-2_2
Weiner ID, Mitch WE, Sands JM. Urea and Ammonia Metabolism and the Control of Renal Nitrogen Excretion. Clin J Am Soc Nephrol. 2015 Aug;10(8):1444.
Rosida A. Pemeriksaan Laboratorium Penyakit Hati. Berk Kedokt. 2016 May 2;12(1):123–31.
Latifah DS, Tirtasari K, Atma CD, Agustin ALD. Deteksi Residu Antibiotik Oksitetrasiklin Pada Hati Ayam Broiler Di Pasar Tradisional Kota Mataram. Mandalika Vet J. 2021 Oct 26;1(2):1–6.
Pribadi A, Sihaloho AA, Rusmiati. Skoring Kerusakan Hati Tikus Jantan (Ratus norvegicus Berkenhout.) setelah Pemberian Ekstrak etanol Daun Supan-supan (Neptunia plena Lour.). Syntax Lit J Ilm Indones. 2023 Jul 13;8(7):5074–81.
Khurana A, Sayed N, Allawadhi P, Weiskirchen R. It’s all about the spaces between cells: role of extracellular matrix in liver fibrosis. Ann Transl Med. 2021 Apr;9(8):728–728.
Liu H, Zhang S, Xu S, Koroleva M, Small EM, Jin ZG. Myofibroblast-specific YY1 promotes liver fibrosis. Biochem Biophys Res Commun. 2019 Jun 30;514(3):913–8.
Mederacke I, Hsu CC, Troeger JS, Huebener P, Mu X, Dapito DH, et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun. 2013 Nov 22;4(1):2823.
Flood HM, Bolte C, Dasgupta N, Sharma A, Zhang Y, Gandhi CR, et al. The forkhead box F1 transcription factor inhibits collagen deposition and accumulation of myofibroblasts during liver fibrosis. Biol Open. 2019 Jan 1;bio.039800.
Xu J, Liu X, Koyama Y, Wang P, Lan T, Kim IG, et al. The types of hepatic myofibroblasts contributing to liver fibrosis of different etiologies. Front Pharmacol [Internet]. 2014 Jul 22 [cited 2025 Mar 4];5. Available from: https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2014.00167/full
Iwaisako K, Taura K, Koyama Y, Takemoto K, Asagiri M. Strategies to Detect Hepatic Myofibroblasts in Liver Cirrhosis of Different Etiologies. Curr Pathobiol Rep. 2014 Dec 1;2(4):209–15.
Cargnoni A, Farigu S, Cotti Piccinelli E, Bonassi Signoroni P, Romele P, Vanosi G, et al. Effect of human amniotic epithelial cells on pro-fibrogenic resident hepatic cells in a rat model of liver fibrosis. J Cell Mol Med. 2018;22(2):1202–13.
Konishi T, Schuster RM, Lentsch AB. Liver repair and regeneration after ischemia-reperfusion injury is associated with prolonged fibrosis. Am J Physiol-Gastrointest Liver Physiol. 2019 Mar;316(3):G323–31.
Liang S, Kisseleva T, Brenner DA. The Role of NADPH Oxidases (NOXs) in Liver Fibrosis and the Activation of Myofibroblasts. Front Physiol [Internet]. 2016 Feb 2 [cited 2025 Mar 3];7. Available from: https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2016.00017/full
Nantasanti S, De Bruin A, Rothuizen J, Penning LC, Schotanus BA. Concise Review: Organoids Are a Powerful Tool for the Study of Liver Disease and Personalized Treatment Design in Humans and Animals. Stem Cells Transl Med. 2016 Mar 1;5(3):325–30.
Koui Y, Kido T, Ito T, Oyama H, Chen SW, Katou Y, et al. An In Vitro Human Liver Model by iPSC-Derived Parenchymal and Non-parenchymal Cells. Stem Cell Rep. 2017 Aug;9(2):490–8.
Tsang HY, Lo PHY, Lee KKH. Generation of liver organoids from human induced pluripotent stem cells as liver fibrosis and steatosis models [Internet]. bioRxiv; 2021 [cited 2025 Mar 3]. p. 2021.06.29.450347. Available from: https://www.biorxiv.org/content/10.1101/2021.06.29.450347v1
Tadokoro T, Murata S, Kato M, Ueno Y, Tsuchida T, Okumura A, et al. Human iPSC–liver organoid transplantation reduces fibrosis through immunomodulation. Sci Transl Med. 2024 Jul 24;16(757):eadg0338.
Bachofner JA, Valli PV, Kröger A, Bergamin I, Künzler P, Baserga A, et al. Direct antiviral agent treatment of chronic hepatitis C results in rapid regression of transient elastography and fibrosis markers fibrosis-4 score and aspartate aminotransferase-platelet ratio index. Liver Int Off J Int Assoc Study Liver. 2017 Mar;37(3):369–76.
Ebrahimi H, Naderian M, Sohrabpour AA. New Concepts on Pathogenesis and Diagnosis of Liver Fibrosis; A Review Article. Middle East J Dig Dis MEJDD. 2016 Jun 11;8(3):166-178. doi: 10.15171/mejdd.2016.29.
Kakinuma S, Watanabe M. Analysis of the mechanism underlying liver diseases using human induced pluripotent stem cells. Immunol Med. 2019 Apr 3;42(2):71–8.
Chehelgerdi M, Behdarvand Dehkordi F, Chehelgerdi M, Kabiri H, Salehian-Dehkordi H, Abdolvand M, et al. Exploring the promising potential of induced pluripotent stem cells in cancer research and therapy. Mol Cancer. 2023 Nov 28;22(1):189.
Chen Z, Jain A, Liu H, Zhao Z, Cheng K. Targeted Drug Delivery to Hepatic Stellate Cells for the Treatment of Liver Fibrosis. J Pharmacol Exp Ther. 2019 Sep 1;370(3):695–702.
Khanam A, Saleeb PG, Kottilil S. Pathophysiology and Treatment Options for Hepatic Fibrosis: Can It Be Completely Cured? Cells. 2021 May 4;10(5):1097.
Liu P, Mao Y, Xie Y, Wei J, Yao J. Stem cells for treatment of liver fibrosis/cirrhosis: clinical progress and therapeutic potential. Stem Cell Res Ther. 2022 Jul 26;13(1):356.
Suominen S, Hyypijev T, Venäläinen M, Yrjänäinen A, Vuorenpää H, Lehti-Polojärvi M, et al. Improvements in Maturity and Stability of 3D iPSC-Derived Hepatocyte-like Cell Cultures. Cells. 2023 Jan;12(19):2368.
Lin Y, Fang ZP, Liu HJ, Wang LJ, Cheng Z, Tang N, et al. HGF/R-spondin1 rescues liver dysfunction through the induction of Lgr5+ liver stem cells. Nat Commun. 2017 Oct 27;8(1):1175.
Takebe T, Sekine K, Kimura M, Yoshizawa E, Ayano S, Koido M, et al. Massive and Reproducible Production of Liver Buds Entirely from Human Pluripotent Stem Cells. Cell Rep. 2017 Dec 5;21(10):2661–70.
Koui Y, Kido T. Using human induced pluripotent stem cell-derived liver cells to investigate the mechanisms of liver fibrosis in vitro. Biochem Soc Trans. 2023 Jun 28;51(3):1271–7.
Vallverdú J, Martínez García de la Torre RA, Mannaerts I, Verhulst S, Smout A, Coll M, et al. Directed differentiation of human induced pluripotent stem cells to hepatic stellate cells. Nat Protoc. 2021 May;16(5):2542–63.
Koui Y, Himeno M, Mori Y, Nakano Y, Saijou E, Tanimizu N, et al. Development of human iPSC-derived quiescent hepatic stellate cell-like cells for drug discovery and in vitro disease modeling. Stem Cell Rep. 2021 Dec 14;16(12):3050–63.
Deguchi S, Takayama K, Mizuguchi H. Generation of Human Induced Pluripotent Stem Cell-Derived Hepatocyte-Like Cells for Cellular Medicine. Biol Pharm Bull. 2020;43(4):608–15.
Nam D, Park MR, Lee H, Bae SC, Gerovska D, Araúzo-Bravo MJ, et al. Induced Endothelial Cell-Integrated Liver Assembloids Promote Hepatic Maturation and Therapeutic Effect on Cholestatic Liver Fibrosis. Cells. 2022 Jan;11(14):2242.
Blackford SJI, Ng SS, Segal JM, King AJF, Austin AL, Kent D, et al. Validation of Current Good Manufacturing Practice Compliant Human Pluripotent Stem Cell-Derived Hepatocytes for Cell-Based Therapy. STEM CELLS Transl Med. 2019;8(2):124–37.
Cayo MA, Mallanna SK, Furio FD, Jing R, Tolliver LB, Bures M, et al. A Drug Screen using Human iPSC-Derived Hepatocyte-like Cells Reveals Cardiac Glycosides as a Potential Treatment for Hypercholesterolemia. Cell Stem Cell. 2017 Apr 6;20(4):478-489.e5.
Broutier L, Mastrogiovanni G, Verstegen MM, Francies HE, Gavarró LM, Bradshaw CR, et al. Human primary liver cancer–derived organoid cultures for disease modeling and drug screening. Nat Med. 2017 Dec;23(12):1424–35.
Prestigiacomo V, Weston A, Messner S, Lampart F, Suter-Dick L. Pro-fibrotic compounds induce stellate cell activation, ECM-remodelling and Nrf2 activation in a human 3D-multicellular model of liver fibrosis. PLOS ONE. 2017 Jun 30;12(6):e0179995.
Norona LM, Nguyen DG, Gerber DA, Presnell SC, Mosedale M, Watkins PB. Bioprinted liver provides early insight into the role of Kupffer cells in TGF-β1 and methotrexate-induced fibrogenesis. PLOS ONE. 2019 Jan 2;14(1):e0208958.
Zhang X, Hu MG, Pan K, Li CH, Liu R. 3D Spheroid Culture Enhances the Expression of Antifibrotic Factors in Human Adipose-Derived MSCs and Improves Their Therapeutic Effects on Hepatic Fibrosis. Stem Cells Int. 2016 Jan 1;2016(1):4626073.
Wang N, Li X, Zhong Z, Qiu Y, Liu S, Wu H, et al. 3D hESC exosomes enriched with miR-6766-3p ameliorates liver fibrosis by attenuating activated stellate cells through targeting the TGFβRII-SMADS pathway. J Nanobiotechnology. 2021 Dec 20;19(1):437.
Zheng W, Bian S, Qiu S, Bishop CE, Wan M, Xu N, et al. Placenta mesenchymal stem cell-derived extracellular vesicles alleviate liver fibrosis by inactivating hepatic stellate cells through a miR-378c/SKP2 axis. Inflamm Regen. 2023 Oct 5;43(1):47.
Sorrentino G, Rezakhani S, Yildiz E, Nuciforo S, Heim MH, Lutolf MP, et al. Mechano-modulatory synthetic niches for liver organoid derivation. Nat Commun. 2020 Jul 10;11(1):3416.
Choi JS, Park YJ, Kim SW. Three-dimensional Differentiated Human Mesenchymal Stem Cells Exhibit Robust Antifibrotic Potential and Ameliorates Mouse Liver Fibrosis. Cell Transplant. 2021 Jan 1;30:0963689720987525.
Lee HJ, Mun SJ, Jung CR, Kang HM, Kwon JE, Ryu JS, et al. In vitro modeling of liver fibrosis with 3D co-culture system using a novel human hepatic stellate cell line. Biotechnol Bioeng. 2023;120(5):1241–53.
Duriez M, Jacquet A, Hoet L, Roche S, Bock MD, Rocher C, et al. A 3D Human Liver Model of Nonalcoholic Steatohepatitis. J Clin Transl Hepatol. 2020 Dec 28;8(4):359–70.
Du C, Feng Y, Qiu D, Xu Y, Pang M, Cai N, et al. Highly efficient and expedited hepatic differentiation from human pluripotent stem cells by pure small-molecule cocktails. Stem Cell Res Ther. 2018 Mar 9;9(1):58.
Hoveizi E, Massumi M, Ebrahimi-barough S, Tavakol S, Ai J. Differential effect of Activin A and WNT3a on definitive endoderm differentiation on electrospun nanofibrous PCL scaffold. Cell Biol Int. 2015;39(5):591–9.
Harrison SP, Siller R, Tanaka Y, Chollet ME, de la Morena-Barrio ME, Xiang Y, et al. Scalable production of tissue-like vascularized liver organoids from human PSCs. Exp Mol Med. 2023 Sep;55(9):2005–24.
Hossam Abdelmonem B, Abdelaal NM, Anwer EKE, Rashwan AA, Hussein MA, Ahmed YF, et al. Decoding the Role of CYP450 Enzymes in Metabolism and Disease: A Comprehensive Review. Biomedicines. 2024 Jul;12(7):1467.
Garrison WD, Battle MA, Yang C, Kaestner KH, Sladek FM, Duncan SA. Hepatocyte Nuclear Factor 4α Is Essential for Embryonic Development of the Mouse Colon. Gastroenterology. 2006 Apr 1;130(4):19.e1-19.e.
An JH, Lee HJ, Jung BH. Quantitative analysis of acetaminophen and its six metabolites in rat plasma using liquid chromatography/tandem mass spectrometry. Biomed Chromatogr. 2012;26(12):1596–604.
Parafati M, Kirby RJ, Khorasanizadeh S, Rastinejad F, Malany S. A nonalcoholic fatty liver disease model in human induced pluripotent stem cell-derived hepatocytes, created by endoplasmic reticulum stress-induced steatosis. Dis Model Mech. 2018 Sep 25;11(9):dmm033530.
Dalton GD, Oh SH, Tang L, Zhang S, Brown AL, Varadharajan V, et al. Hepatocyte activity of the cholesterol sensor smoothened regulates cholesterol and bile acid homeostasis in mice. iScience [Internet]. 2021 Sep 24 [cited 2025 Mar 3];24(9). Available from: https://www.cell.com/iscience/abstract/S2589-0042(21)01057-9
Klepikova A, Nenasheva T, Sheveleva O, Protasova E, Antonov D, Gainullina A, et al. iPSC-Derived Macrophages: The Differentiation Protocol Affects Cell Immune Characteristics and Differentiation Trajectories. Int J Mol Sci. 2022 Jan;23(24):16087.
Cao X, Yakala GK, Hil FE van den, Cochrane A, Mummery CL, Orlova VV. Differentiation and Functional Comparison of Monocytes and Macrophages from hiPSCs with Peripheral Blood Derivatives. Stem Cell Rep. 2019 Jun 11;12(6):1282–97.
Cassetta L, Cassol E, Poli G. Macrophage Polarization in Health and Disease. Sci World J. 2011;11(1):213962.
Ambarus CA, Krausz S, van Eijk M, Hamann J, Radstake TRDJ, Reedquist KA, et al. Systematic validation of specific phenotypic markers for in vitro polarized human macrophages. J Immunol Methods. 2012 Jan 31;375(1):196–206.
Cutolo M, Campitiello R, Gotelli E, Soldano S. The Role of M1/M2 Macrophage Polarization in Rheumatoid Arthritis Synovitis. Front Immunol [Internet]. 2022 May 19 [cited 2025 Mar 3];13. Available from: https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.867260/full
Yang Z, Ming XF. Functions of Arginase Isoforms in Macrophage Inflammatory Responses: Impact on Cardiovascular Diseases and Metabolic Disorders. Front Immunol [Internet]. 2014 Oct 27 [cited 2025 Mar 3];5. Available from: https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2014.00533/full
Li S, Song L, Zhang Y, Zhan Z, Yang Y, Yu L, et al. Optimizing the Method for Differentiation of Macrophages from Human Induced Pluripotent Stem Cells. Stem Cells Int. 2022;2022(1):6593403.
Lachmann N, Ackermann M, Frenzel E, Liebhaber S, Brennig S, Happle C, et al. Large-Scale Hematopoietic Differentiation of Human Induced Pluripotent Stem Cells Provides Granulocytes or Macrophages for Cell Replacement Therapies. Stem Cell Rep. 2015 Feb 10;4(2):282–96.
Panicker LM, Miller D, Awad O, Bose V, Lun Y, Park TS, et al. Gaucher iPSC-derived macrophages produce elevated levels of inflammatory mediators and serve as a new platform for therapeutic development. Stem Cells Dayt Ohio. 2014 Sep;32(9):2338–49.
Cai J, Huang L, Tang H, Xu H, Wang L, Zheng M, et al. Macrophage migration inhibitory factor of Thelazia callipaeda induces M2-like macrophage polarization through TLR4-mediated activation of the PI3K-Akt pathway. FASEB J. 2021;35(9):e21866.
Cerdan C, McIntyre BAS, Mechael R, Levadoux-Martin M, Yang J, Lee JB, et al. Activin A Promotes Hematopoietic Fated Mesoderm Development Through Upregulation of Brachyury in Human Embryonic Stem Cells. Stem Cells Dev. 2012 Oct 10;21(15):2866–77.
Kamm DR, McCommis KS. Hepatic stellate cells in physiology and pathology. J Physiol. 2022;600(8):1825–37.
Schachtrup C, Le Moan N, Passino MA, Akassoglou K. Hepatic stellate cells and astrocytes: Stars of scar formation and tissue repair. Cell Cycle. 2011 Jun 1;10(11):1764–71.
Higashi T, Friedman SL, Hoshida Y. Hepatic stellate cells as key target in liver fibrosis. Adv Drug Deliv Rev. 2017 Nov 1;121:27–42.
Dewidar B, Meyer C, Dooley S, Meindl-Beinker and N. TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019. Cells. 2019 Nov;8(11):1419.
Lee YS, Seki E. In Vivo and In Vitro Models to Study Liver Fibrosis: Mechanisms and Limitations. Cell Mol Gastroenterol Hepatol. 2023 Jan 1;16(3):355–67.
Orlova VV, Drabsch Y, Freund C, Petrus-Reurer S, van den Hil FE, Muenthaisong S, et al. Functionality of Endothelial Cells and Pericytes From Human Pluripotent Stem Cells Demonstrated in Cultured Vascular Plexus and Zebrafish Xenografts. Arterioscler Thromb Vasc Biol. 2014 Jan;34(1):177–86.
Patsch C, Challet-Meylan L, Thoma EC, Urich E, Heckel T, O’Sullivan JF, et al. Generation of vascular endothelial and smooth muscle cells from human pluripotent stem cells. Nat Cell Biol. 2015 Aug;17(8):994–1003.
Rieck S, Sharma K, Altringer C, Hesse M, Triantafyllou C, Zhang Y, et al. Forward programming of human induced pluripotent stem cells via the ETS variant transcription factor 2: rapid, reproducible, and cost-effective generation of highly enriched, functional endothelial cells. Cardiovasc Res. 2024 Aug 1;120(12):1472–84.
Yap KK, Schröder J, Gerrand YW, Dobric A, Kong AM, Fox AM, et al. Liver specification of human iPSC-derived endothelial cells transplanted into mouse liver. JHEP Rep [Internet]. 2024 May 1 [cited 2025 Mar 3];6(5). Available from: https://www.jhep-reports.eu/article/S2589-5559(24)00024-7/fulltext
Shi Y, Deng J, Sang X, Wang Y, He F, Chen X, et al. Generation of Hepatocytes and Nonparenchymal Cell Codifferentiation System from Human-Induced Pluripotent Stem Cells. Stem Cells Int. 2022;2022(1):3222427.
Halaidych OV, Freund C, Hil F van den, Salvatori DCF, Riminucci M, Mummery CL, et al. Inflammatory Responses and Barrier Function of Endothelial Cells Derived from Human Induced Pluripotent Stem Cells. Stem Cell Rep. 2018 May 8;10(5):1642–56.
Duinen V van, Stam W, Borgdorff V, Reijerkerk A, Orlova V, Vulto P, et al. Standardized and Scalable Assay to Study Perfused 3D Angiogenic Sprouting of iPSC-derived Endothelial Cells In Vitro. J Vis Exp JoVE. 2019 Nov 6;(153):e59678.
Rapp J, Ness J, Liang P, Hug MJ, Agostini H, Schlunck G, et al. Investigating Angiogenesis on a Functional and Molecular Level by Leveraging the Scratch Wound Migration Assay and the Spheroid Sprouting Assay. J Vis Exp JoVE. 2024 May 31;(207):e66954.
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