Abstract
Stem cells are characterized by their self-renewal capacity and their ability to differentiate into multiple cell types of the human body. Using directed differentiation strategies, stem cells can now be converted into hepatocyte-like cells (HLCs) and therefore, represent a unique cell source for toxicological applications in vitro. However, the acquired hepatic functionality of stem cell-derived HLCs is still significantly inferior to primary human hepatocytes. One of the main reasons for this is that most in vitro models use traditional two-dimensional (2D) setups where the flat substrata cannot properly mimic the physiology of the human liver. Therefore, 2D-setups are progressively being replaced by more advanced culture systems, which attempt to replicate the natural liver microenvironment, in which stem cells can better differentiate towards HLCs. This review highlights the most recent cell culture systems, including scaffold-free and scaffold-based three-dimensional (3D) technologies and microfluidics that can be employed for culture and hepatic differentiation of stem cells intended for hepatotoxicity testing. These methodologies have shown to improve in vitro liver cell functionality according to the in vivo liver physiology and allow to establish stem cell-based hepatic in vitro platforms for the accurate evaluation of xenobiotics.
This is a preview of subscription content, log in via an institution to check access.
Image modified from The ibidi Product and Experiment Guide (https://ibidi.com/)
Similar content being viewed by others
Abbreviations
- 2D:
-
Two-dimensional
- 2PP:
-
Two-photon polymerization
- 3D:
-
Three-dimensional
- ADMSCs:
-
Adipose-derived mesenchymal stem cells
- ASCs:
-
Adult human stem cells
- BMMSCs:
-
Bone marrow mesenchymal stem cells
- BMP:
-
Bone morphogenetic protein
- BSEP:
-
Bile salt export pump
- CFOS:
-
Proto-oncogene c-fos
- CYP:
-
Cytochrome P450
- ECM:
-
Extracellular matrix
- EGR:
-
Early growth response
- FGF:
-
Fibroblast growth factor
- Gel-MOD:
-
Methacrylamide-gelatin
- Gel-MOD-AEMA:
-
Gelatin-methacrylamide-aminoethylmethacrylate
- Gel-NB:
-
Gel-Norbornene
- hESCs:
-
Human embryonic stem cells
- HGF:
-
Hepatic growth factor
- hiPSCs:
-
Human induced pluripotent stem cells
- HLCs:
-
Hepatocyte-like cells
- hMSCs:
-
Human mesenchymal stem/stromal cells
- hSKP:
-
Human skin-derived precursors
- IEG:
-
Immediate early genes
- MenSCs:
-
Menstrual blood stem cells
- MPCCs:
-
Micropatterned co-cultures
- NTCP:
-
Sodium-taurocholate cotransporting polypeptide
- OSM:
-
Oncostatin M
- PAI:
-
Plasminogen activator inhibitor
- PDMSCs:
-
Placenta-derived mesenchymal stem cells
- PHH:
-
Primary human hepatocytes
- PRL:
-
Phosphatase of regenerating liver
- UCMSCs:
-
Umbilical cord mesenchymal stem cells
- Wnt:
-
Wingless-type MMTV integration site
References
Abbott A (2003) Biology’s new dimension. Nature 424:870–872. https://doi.org/10.1038/424870a
Antoni D, Burckel H, Josset E, Noel G (2015) Three-dimensional cell culture: a breakthrough in vivo. Int J Mol Sci 16:5517–5527. https://doi.org/10.3390/ijms16035517
Asai A, Aihara E, Watson C et al (2017) Paracrine signals regulate human liver organoid maturation from induced pluripotent stem cells. Development 144:1056–1064. https://doi.org/10.1242/dev.142794
Asti A, Gioglio L (2014) Natural and synthetic biodegradable polymers: different scaffolds for cell expansion and tissue formation. Int J Artif Organs 37:187–205. https://doi.org/10.530/ijao.5000307
Azandeh S, Gharravi AM, Orazizadeh M et al (2016) Improvement of mesenchymal stem cell differentiation into the endoderm lineage by four step sequential method in biocompatible biomaterial. BioImpacts 6:9–13. https://doi.org/10.15171/bi.2016.02
Baharvand H, Hashemi SM, Ashtiani SK, Farrokhi A (2006) Differentiation of human embryonic stem cells into hepatocytes in 2D and 3D culture systems in vitro. Int J Dev Biol 50:645–652. https://doi.org/10.1387/ijdb.052072hb
Banaeiyan AA, Theobald J, Paukštyte J et al (2017) Design and fabrication of a scalable liver-lobule-on-a-chip microphysiological platform. Biofabrication 9:015014. https://doi.org/10.1088/1758-5090/9/1/015014
Baptista PM, Siddiqui MM, Lozier G et al (2011) The use of whole organ decellularization for the generation of a vascularized liver organoid. Hepatology 53:604–617. https://doi.org/10.1002/hep.24067
Baxter MA, Rowe C, Alder J et al (2010) Generating hepatic cell lineages from pluripotent stem cells for drug toxicity screening. Stem Cell Res 5:4–22. https://doi.org/10.1016/j.scr.2010.02.002
Behbahan IS, Duan Y, Lam A et al (2011) New approaches in the differentiation of human embryonic stem cells and induced pluripotent stem cells toward hepatocytes. Stem Cell Rev Rep 7:748–759. https://doi.org/10.1007/s12015-010-9216-4
Berger DR, Ware BR, Davidson MD et al (2015) Enhancing the functional maturity of induced pluripotent stem cell-derived human hepatocytes by controlled presentation of cell–cell interactions in vitro. Hepatology 61:1370–1381. https://doi.org/10.1002/hep.27621
Bishi DK, Mathapati S, Venugopal JR et al (2013) Trans-differentiation of human mesenchymal stem cells generates functional hepatospheres on poly(l-lactic acid)-co-poly(ε-caprolactone)/collagen nanofibrous scaffolds. J Mater Chem B 1:3972–3984. https://doi.org/10.1039/c3tb20241k
Buzgo M, Rampichova M, Vocetkova K et al (2017) Emulsion centrifugal spinning for production of 3D drug releasing nanofibres with core/shell structure. RSC Adv 7:1215–1228. https://doi.org/10.1039/C6RA26606A
Caliari RS, Burdick AJ (2016) A practical guide to hydrogels for cell culture. Nat Methods 13:405–414. https://doi.org/10.1038/nmeth.3839
Caplan AI (2015) Are all adult stem cells the same? Regen Eng Transl Med 1:4–10. https://doi.org/10.1007/s40883-015-0001-4
Castell JV, Jover R, Martnez-Jimnez CP, Gomez-Lechon MJ (2006) Hepatocyte cell lines: their use, scope and limitations in drug metabolism studies. Expert Opin Drug Metab Toxicol 2:183–212. https://doi.org/10.1517/17425255.2.2.183
Chang R, Chou M, Hung L et al (2016) Study of valproic acid-enhanced hepatocyte steatosis. Biomed Res Int 2016:9576503. https://doi.org/10.1155/2016/9576503
Chen Z, Sun M, Yuan Q et al (2016) Generation of functional hepatocytes from human spermatogonial stem cells. Oncotarget 7:8879–8895. https://doi.org/10.18632/oncotarget.7092
Chitrangi S, Nair P, Khanna A (2017) 3D engineered in vitro hepatospheroids for studying drug toxicity and metabolism. Toxicol In Vitro 38:8–18. https://doi.org/10.1016/j.tiv.2016.10.009
Cozzolino AM, Noce V, Battistelli C et al (2016) Modulating the substrate stiffness to manipulate differentiation of resident liver stem cells and to improve the differentiation state of hepatocytes. Stem Cells Int 2016:5481493. https://doi.org/10.1155/2016/5481493
Dahlin RL, Kasper FK, Mikos AG (2011) Polymeric nanofibers in tissue engineering. Tissue Eng Part B Rev 17:349–364. https://doi.org/10.1089/ten.TEB.2011.0238
Damania A, Jain E, Kumar A (2014) Advancements in in vitro hepatic models: application for drug screening and therapeutics. Hepatol Int 8:23–38. https://doi.org/10.1007/s12072-013-9490-8
Davila JC, Cezar GG, Thiede M et al (2004) Use and application of stem cells in toxicology. Toxicol Sci 79:214–223. https://doi.org/10.1093/toxsci/kfh100
De Kock J, Ceelen L, De Spiegelaere W et al (2011) Simple and quick method for whole-liver decellularization: a novel in vitro three-dimensional bioengineering tool? Arch Toxicol 85:607–612. https://doi.org/10.1007/s00204-011-0706-1
Deegan DB, Zimmerman C, Skardal A et al (2015) Stiffness of hyaluronic acid gels containing liver extracellular matrix supports human hepatocyte function and alters cell morphology. J Mech Behav Biomed Mater 55:87–103. https://doi.org/10.1016/j.jmbbm.2015.10.016
Denayer T, Stohr T, Van Roy M (2014) Animal models in translational medicine: validation and prediction. New Horizons Transl Med 2:5–11. https://doi.org/10.1016/j.nhtm.2014.08.001
Dhandayuthapani B, Yoshida Y, Maekawa T, Kumar DS (2011) Polymeric scaffolds in tissue engineering application: a review. Int J Polym Sci 2011:290602. https://doi.org/10.1155/2011/290602
Divya MS, Roshin GE, Divya TS et al (2012) Umbilical cord blood-derived mesenchymal stem cells consist of a unique population of progenitors co-expressing mesenchymal stem cell and neuronal markers capable of instantaneous neuronal differentiation. Stem Cell Res Ther 3:57. https://doi.org/10.1186/scrt148
Doke SK, Dhawale SC (2015) Alternatives to animal testing: a review. Saudi Pharm J 23:223–229. https://doi.org/10.1016/j.jsps.2013.11.002
Du C, Feng Y, Qiu D et al (2018) Highly efficient and expedited hepatic differentiation from human pluripotent stem cells by pure small-molecule cocktails. Stem Cell Res Ther 9:58. https://doi.org/10.1186/s13287-018-0794-4
Duval K, Grover H, Han L-H et al (2017) Modeling physiological events in 2D vs. 3D cell culture. Physiology (Bethesda) 32:266–277. https://doi.org/10.1152/physiol.00036.2016
Eipel C, Abshagen K, Vollmar B (2010) Regulation of hepatic blood flow: the hepatic arterial buffer response revisited. World J Gastroenterol 16:6046–6057. https://doi.org/10.3748/wjg.v16.i48.6046
Fan C, Wang D-A (2017) Macroporous hydrogel scaffolds for three-dimensional cell culture and tissue engineering. Tissue Eng Part B Rev 23:451–461. https://doi.org/10.1089/ten.teb.2016.0465
Fang Y, Eglen RM (2017) Three-dimensional cell cultures in drug discovery and development. SLAS Discov 22:456–472. https://doi.org/10.1177/1087057117696795
Faulkner-Jones A, Fyfe C, Cornelissen D-J et al (2015) Bioprinting of human pluripotent stem cells and their directed differentiation into hepatocyte-like cells for the generation of mini-livers in 3D. Biofabrication 7:044102. https://doi.org/10.1088/1758-5090/7/4/044102
Freyer N, Knöspel F, Strahl N et al (2016) Hepatic differentiation of human induced pluripotent stem cells in a perfused three-dimensional multicompartment bioreactor. Biores Open Access 5:235–248. https://doi.org/10.1089/biores.2016.0027
Garreta E, Oria R, Tarantino C et al (2017) Tissue engineering by decellularization and 3D bioprinting. Mater Today 20:166–178. https://doi.org/10.1016/j.mattod.2016.12.005
Gasperini L, Mano JF, Reis RL (2014) Natural polymers for the microencapsulation of cells. J R Soc Interface 11:20140817. https://doi.org/10.1098/rsif.2014.0817
Gerecht S, Burdick JA, Ferreira LS et al (2007) Hyaluronic acid hydrogel for controlled self-renewal and differentiation of human embryonic stem cells. Proc Natl Acad Sci USA 104:11298–11303. https://doi.org/10.1073/pnas.0703723104
Ghaedi M, Soleimani M, Shabani I et al (2012) Hepatic differentiation from human mesenchymal stem cells on a novel nanofiber scaffold. Cell Mol Biol Lett 17:89–106. https://doi.org/10.2478/s11658-011-0040-x
Giobbe GG, Michielin F, Luni C et al (2015) Functional differentiation of human pluripotent stem cells on a chip. Nat Methods 12:637–640. https://doi.org/10.1038/nmeth.3411
Godoy P, Hewitt NJ, Albrecht U et al (2013) Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME. Arch Toxicol 87:1315–1530. https://doi.org/10.1007/s00204-013-1078-5
Gómez-Lechón M, Tolosa L, Donato M (2014) Cell-based models to predict human hepatotoxicity of drugs. Rev Toxicol 31:149–156. http://www.redalyc.org/articulo.oa?id=91932969007. Accessed 26 Apr 2019. ISSN:0212-7113
Guguen-guillouzo C, Corlu A, Guillouzo A (2010) Stem cell-derived hepatocytes and their use in toxicology. Toxicology 270:3–9. https://doi.org/10.1016/j.tox.2009.09.019
Gupta N, Liu JR, Patel B et al (2016) Microfluidics-based 3D cell culture models: utility in novel drug discovery and delivery research. Bioeng Transl Med 1:63–81. https://doi.org/10.1002/btm2.10013
Hartung T (2009) Toxicology for the twenty-first century. Nature 460:208–212. https://doi.org/10.1038/460208a
Hashemi SM, Soleimani M, Zargarian SS et al (2009) In vitro differentiation of human cord blood-derived unrestricted somatic stem cells into hepatocyte-like cells on poly(e-caprolactone) nanofiber scaffolds. Cells Tissues Organs 190:135–149. https://doi.org/10.1159/000187716
Hay M, Thomas DW, Craighead JL et al (2014) Clinical development success rates for investigational drugs. Nat Biotechnol 32:40–51. https://doi.org/10.1038/nbt.2786
He H, Liu X, Peng L et al (2013) Promotion of hepatic differentiation of bone marrow mesenchymal stem cells on decellularized cell-deposited extracellular matrix. Biomed Res Int 2013:406871. https://doi.org/10.1155/2013/406871
Hindley CJ, Cordero-Espinoza L, Huch M (2016) Organoids from adult liver and pancreas: stem cell biology and biomedical utility. Dev Biol 420:251–261. https://doi.org/10.1016/j.ydbio.2016.06.039
Holmgren G, Sjogren A-K, Barragan I, Sabirsh A (2014) Long-term chronic toxicity testing using human pluripotent stem cell-derived hepatocytes. Drug Metab Dispos 42:1401–1406. https://doi.org/10.1124/dmd.114.059154
Horvath P, Aulner N, Bickle M et al (2016) Screening out irrelevant cell-based models of disease. Nat Rev Drug Discov 15:751–769. https://doi.org/10.1038/nrd.2016.175
Hoshiba T, Chen G, Endo C et al (2016) Decellularized extracellular matrix as an in vitro model to study the comprehensive roles of the ECM in stem cell differentiation. Stem Cells Int 2016:6397820. https://doi.org/10.1155/2016/6397820
Huang P, Zhang L, Gao Y et al (2014) Direct reprogramming of human fibroblasts to functional and expandable hepatocytes. Cell Stem Cell 14:370–384. https://doi.org/10.1016/j.stem.2014.01.003
Huch M, Gehart H, Van Boxtel R et al (2015) Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell 160:299–312. https://doi.org/10.1016/j.cell.2014.11.050
Ikeda K, Nagata S, Okitsu T, Takeuchi S (2017) Cell fiber-based three-dimensional culture system for highly efficient expansion of human induced pluripotent stem cells. Sci Rep 7:2850. https://doi.org/10.1038/s41598-017-03246-2
Inamura M, Kawabata K, Takayama K et al (2011) Efficient generation of hepatoblasts from human ES cells and iPS cells by transient overexpression of homeobox gene HEX. Mol Ther 19:400–407. https://doi.org/10.1038/mt.2010.241
Itaba N, Matsumi Y, Okinaka K et al (2015) Human mesenchymal stem cell-engineered hepatic cell sheets accelerate liver regeneration in mice. Sci Rep 5:16169. https://doi.org/10.1038/srep16169
Jain E, Damania A, Kumar A (2014) Biomaterials for liver tissue engineering. Hepatol Int 8:185–197. https://doi.org/10.1007/s12072-013-9503-7
Jeon O, Alt DS, Linderman SW, Alsberg E (2013) Biochemical and physical signal gradients in hydrogels to control stem cell behavior. Adv Mater 25:6366–6372. https://doi.org/10.1002/adma.201302364
Ju X, Li D, Gao N et al (2008) Hepatogenic differentiation of mesenchymal stem cells using microfluidic chips. Biotechnol J 3:383–391. https://doi.org/10.1002/biot.200700152
Kamiya A, Kinoshita T, Miyajima A (2001) Oncostatin M and hepatocyte growth factor induce hepatic maturation via distinct signaling pathways. FEBS Lett 492:90–94. https://doi.org/10.1016/S0014-5793(01)02140-8
Kazemnejad S, Allameh A, Soleimani M et al (2009) Biochemical and molecular characterization of hepatocyte-like cells derived from human bone marrow mesenchymal stem cells on a novel three-dimensional biocompatible nanofibrous scaffold. J Gastroenterol Hepatol 24:278–287. https://doi.org/10.1111/j.1440-1746.2008.05530.x
Khetani SR, Bhatia SN (2008) Microscale culture of human liver cells for drug development. Nat Biotechnol 26:120–126. https://doi.org/10.1038/nbt1361
Kim JH, Wang M, Lee J et al (2018) Prediction of hepatotoxicity for drugs using human pluripotent stem cell-derived hepatocytes. Cell Biol Toxicol 34:51–64. https://doi.org/10.1007/s10565-017-9392-y
Knight E, Przyborski S (2015) Advances in 3D cell culture technologies enabling tissue-like structures to be created in vitro. J Anat 227:746–756. https://doi.org/10.1111/joa.12257
Koch A, Horn A, Dückers H et al (2011) Increased liver stiffness denotes hepatic dysfunction and mortality risk in critically ill noncirrhotic patients at a medical ICU. Crit Care 15:R266. https://doi.org/10.1186/cc10543
Koroleva A, Deiwick A, Nguyen A et al (2015) Osteogenic differentiation of human mesenchymal stem cells in 3-D Zr–Si organic-inorganic scaffolds produced by two-photon polymerization technique. PLoS ONE 10:e0118164. https://doi.org/10.1371/journal.pone.0118164
Kretzschmar K, Clevers H (2016) Organoids: modeling development and the stem cell niche in a dish. Dev Cell 38:590–600. https://doi.org/10.1016/j.devcel.2016.08.014
Langhans SA (2018) Three-dimensional in vitro cell culture models in drug discovery and drug repositioning. Front Pharmacol 9:6. https://doi.org/10.3389/fphar.2018.00006
Lanzoni G, Cardinale V, Carpino G (2016) The hepatic, biliary, and pancreatic network of stem/progenitor cell niches in humans: a new reference frame for disease and regeneration. Hepatology 64:277–286. https://doi.org/10.1002/hep.28326
Leberfinger AN, Ravnic DJ, Dhawan A, Ozbolat IT (2017) Concise review: bioprinting of stem cells for transplantable tissue fabrication. Stem Cells Transl Med 6:1940–1948. https://doi.org/10.1002/sctm.17-0148
Lee K-D, Kuo TK-C, Whang-Peng J et al (2004) In vitro hepatic differentiation of human mesenchymal stem cells. Hepatology 40:1275–1284. https://doi.org/10.1002/hep.20469
Lee HJ, Cha KE, Hwang SG et al (2011) In vitro screening system for hepatotoxicity: comparison of bone-marrow-derived mesenchymal stem cells and placenta-derived stem cells. J Cell Biochem 112:49–58. https://doi.org/10.1002/jcb.22728
Lee HJ, Son MJ, Ahn J et al (2017) Elasticity-based development of functionally enhanced multicellular 3D liver encapsulated in hybrid hydrogel. Acta Biomater 64:67–79. https://doi.org/10.1016/j.actbio.2017.09.041
Leino M, Astrand C, Hughes-Brittain N et al (2018) Human embryonic stem cell dispersion in electrospun PCL fiber scaffolds by coating with laminin-521 and E-cadherin-Fc. J Biomed Mater Res B Appl Biomater 106:1226–1236. https://doi.org/10.1002/jbm.b.33928
Li WJ, Tuli R, Huang X et al (2005) Multilineage differentiation of human mesenchymal stem cells in a three-dimensional nanofibrous scaffold. Biomaterials 26:5158–5166. https://doi.org/10.1016/j.biomaterials.2005.01.002
Li J, Tao R, Wu W et al (2010) 3D PLGA scaffolds improve differentiation and function of bone marrow mesenchymal stem cell-derived hepatocytes. Stem Cells Dev 19:1427–1436. https://doi.org/10.1089/scd.2009.0415
Lin C, Khetani SR (2016) Advances in engineered liver models for investigating drug-induced liver injury. Biomed Res Int 2016:1829148. https://doi.org/10.1155/2016/1829148
Lin H, Yang G, Tan J, Tuan RS (2012) Influence of decellularized matrix derived from human mesenchymal stem cells on their proliferation, migration and multi-lineage differentiation potential. Biomaterials 33:4480–4489. https://doi.org/10.1016/j.biomaterials.2012.03.012
Loh QL, Choong C (2013) Three-dimensional scaffolds for tissue engineering applications: role of porosity and pore size. Tissue Eng Part B Rev 19:485–502. https://doi.org/10.1089/ten.teb.2012.0437
Lu T, Li Y, Chen T (2013) Techniques for fabrication and construction of three-dimensional scaffolds for tissue engineering. Int J Nanomed 8:337–350. https://doi.org/10.2147/IJN.S38635
Lu HF, Leong M, Lim T et al (2017) Engineering a functional three-dimensional human cardiac tissue model for drug toxicity screening. Biofabrication 9:025011. https://doi.org/10.1088/1758-5090/aa6c3a
Lucendo-Villarin B, Rashidi H, Cameron K, Hay DC (2016) Pluripotent stem cell derived hepatocytes: using materials to define cellular differentiation and tissue engineering. J Mater Chem B 4:3433–3442. https://doi.org/10.1039/c6tb00331a
Luni C, Giulitti S, Serena E et al (2016) High-efficiency cellular reprogramming with microfluidics. Nat Methods 13:446–452. https://doi.org/10.1038/nmeth.3832
Lysy PA, Smets F, Najimi M, Sokal EM (2008) Leukemia inhibitory factor contributes to hepatocyte-like differentiation of human bone marrow mesenchymal stem cells. Differentiation 76:1057–1067. https://doi.org/10.1111/j.1432-0436.2008.00287.x
Ma X, Qu X, Zhu W et al (2016) Deterministically patterned biomimetic human iPSC-derived hepatic model via rapid 3D bioprinting. Proc Natl Acad Sci USA 113:2206–2211. https://doi.org/10.1073/pnas.1524510113
Maguire TJ, Novik EI, Schloss R et al (2005) Alginate encapsulation and hepatic differentiation of embryonic stem cells. In: IEEE 31st annual northeast bioengineering conference. https://doi.org/10.1109/nebc.2005.1431997
Maruo S, Fourkas JT (2008) Recent progress in multiphoton microfabrication. Laser Photonics Rev 2:100–111. https://doi.org/10.1002/lpor.200710039
Mathapati S, Siller R, Impellizzeri AA et al (2016) Small-molecule-directed hepatocyte-like cell differentiation of human pluripotent stem cells. Curr Protoc Stem Cell Biol 38:1G.6.1–1G.6.18. https://doi.org/10.1002/cpsc.13
Mazza G, Rombouts K, Rennie Hall A et al (2015) Decellularized human liver as a natural 3D-scaffold for liver bioengineering and transplantation. Sci Rep 5:13079. https://doi.org/10.1038/srep13079
Medine CN, Lucendo-Villarin B, Storck C et al (2013) Developing high-fidelity hepatotoxicity models from pluripotent stem cells. Stem Cells Transl Med 2:505–509. https://doi.org/10.5966/sctm.2012-0138
Meissner A, Wernig M, Jaenisch R (2007) Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Nat Biotechnol 25:1177–1181. https://doi.org/10.1038/nbt1335
Miki T, Ring A, Gerlach J (2011) Hepatic differentiation of human embryonic stem cells is promoted by three-dimensional dynamic perfusion culture conditions. Tissue Eng Part C Methods 17:557–568. https://doi.org/10.1089/ten.tec.2010.0437
Mou X, Lin J, Chen JY et al (2013) Menstrual blood-derived mesenchymal stem cells differentiate into functional hepatocyte-like cells. J Zhejiang Univ Sci B 14:961–972. https://doi.org/10.1631/jzus.B1300081
Mueller S, Sandrin L (2010) Liver stiffness: a novel parameter for the diagnosis of liver disease. Hepatic Med Evid Res 2:49–67. https://doi.org/10.2147/HMER.S7394
Nair LS, Bhattacharyya S, Laurencin CT (2004) Development of novel tissue engineering scaffolds via electrospinning. Expert Opin Biol Ther 4:659–668. https://doi.org/10.1517/14712598.4.5.659
Nakamori D, Akamine H, Takayama K et al (2017) Direct conversion of human fibroblasts into hepatocyte-like cells by ATF5, PROX1, FOXA2, FOXA3, and HNF4A transduction. Sci Rep 7:16675. https://doi.org/10.1038/s41598-017-16856-7
Nakatsuka H, Sokabe T, Yamamoto K et al (2006) Shear stress induces hepatocyte PAI-1 gene expression through cooperative Sp1/Ets-1 activation of transcription. AJP Gastrointest Liver Physiol 291:G26–G34. https://doi.org/10.1152/ajpgi.00467.2005
Nantasanti S, de Bruin A, Rothuizen J et al (2016) 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 5:325–330. https://doi.org/10.5966/sctm.2015-0152
Natale A, Boeckmans J, Desmae T et al (2017) Hepatic cells derived from human skin progenitors show a typical phospholipidotic response upon exposure to amiodarone. Toxicol Lett 284:184–194. https://doi.org/10.1016/j.toxlet.2017.11.014
Nava MM, Raimondi MT, Credi C et al (2015) Interactions between structural and chemical biomimetism in synthetic stem cell niches. Biomed Mater 10:015012. https://doi.org/10.1088/1748-6041/10/1/015012
Navarro-Tableros V, Herrera Sanchez MB, Figliolini F et al (2015) Recellularization of rat liver scaffolds by human liver stem cells. Tissue Eng Part A 21:1929–1939. https://doi.org/10.1089/ten.tea.2014.0573
Nicodemus GD, Bryant SJ (2008) Cell encapsulation in biodegradable hydrogels for tissue engineering applications. Tissue Eng Part B Rev 14:149–165. https://doi.org/10.1089/ten.teb.2007.0332
Nie YZ, Zheng YW, Ogawa M et al (2018) Human liver organoids generated with single donor-derived multiple cells rescue mice from acute liver failure. Stem Cell Res Ther 9:5. https://doi.org/10.1186/s13287-017-0749-1
Nishii K, Brodin E, Renshaw T et al (2018) Shear stress upregulates regeneration-related immediate early genes in liver progenitors in 3D ECM-like microenvironments. J Cell Physiol 233:4272–4281. https://doi.org/10.1002/jcp.26246
Ong LJY, Chong LH, Jin L et al (2017) A pump-free microfluidic 3D perfusion platform for the efficient differentiation of human hepatocyte-like cells. Biotechnol Bioeng 114:2360–2370. https://doi.org/10.1002/bit.26341
Ovsianikov A, Deiwick A, Van Vlierberghe S et al (2011) Laser fabrication of 3D gelatin scaffolds for the generation of bioartificial tissues. Materials (Basel) 4:288–299. https://doi.org/10.3390/ma4010288
Parmar PA, Chow LW, St-Pierre JP et al (2015) Collagen-mimetic peptide-modifiable hydrogels for articular cartilage regeneration. Biomaterials 54:213–225. https://doi.org/10.1016/j.biomaterials.2015.02.079
Rampichová M, Buzgo M, Chvojka J et al (2014) Cell penetration to nanofibrous scaffolds: Forcespinning®, an alternative approach for fabricating 3D nanofibers. Cell Adhes Migr 8:36–41. https://doi.org/10.4161/cam.27477
Rashidi H, Alhaque S, Szkolnicka D et al (2016) Fluid shear stress modulation of hepatocyte-like cell function. Arch Toxicol 90:1757–1761. https://doi.org/10.1007/s00204-016-1689-8
Rimann M, Graf-Hausner U (2012) Synthetic 3D multicellular systems for drug development. Curr Opin Biotechnol 23:803–809. https://doi.org/10.1016/j.copbio.2012.01.011
Rodrigues RM, De Kock J, Branson S et al (2014) Human skin-derived stem cells as a novel cell source for in vitro hepatotoxicity screening of pharmaceuticals. Stem Cells Dev 23:44–55. https://doi.org/10.1089/scd.2013.0157
Rodrigues RM, Branson S, De Boe V et al (2016) In vitro assessment of drug-induced liver steatosis based on human dermal stem cell-derived hepatic cells. Arch Toxicol 90:677–689. https://doi.org/10.1007/s00204-015-1483-z
Sato Y, Tsukada K, Hatakeyama K (1999) Role of shear stress and immune responses in liver regeneration after a partial hepatectomy. Surg Today 29:1–9. https://doi.org/10.1007/BF02482962
Schlie S, Ngezahayo A, Ovsianikov A et al (2007) Three-dimensional cell growth on structures fabricated from ORMOCER® by two-photon polymerization technique. J Biomater Appl 22:275–287. https://doi.org/10.1177/0885328207077590
Schwartz RE, Reyes M, Koodie L et al (2002) Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Investig 109:1291–1302. https://doi.org/10.1172/JCI15182
Selimis A, Mironov V, Farsari M (2015) Direct laser writing: principles and materials for scaffold 3D printing. Microelectron Eng 132:83–89. https://doi.org/10.1016/j.mee.2014.10.001
Sengupta S, Johnson BP, Swanson SA et al (2014) Aggregate culture of human embryonic stem cell-derived hepatocytes in suspension are an improved in vitro model for drug metabolism and toxicity testing. Toxicol Sci 140:236–245. https://doi.org/10.1093/toxsci/kfu069
Sgodda M, Dai Z, Zweigerdt R et al (2017) A scalable approach for the generation of human pluripotent stem cell-derived hepatic organoids with sensitive hepatotoxicity features. Stem Cells Dev 26:1490–1504. https://doi.org/10.1089/scd.2017.0023
Shinozawa T, Yoshikawa HY, Takebe T (2016) Reverse engineering liver buds through self-driven condensation and organization towards medical application. Dev Biol 420:221–229. https://doi.org/10.1016/j.ydbio.2016.06.036
Siller R, Greenhough S, Naumovska E, Sullivan GJ (2015) Small-molecule-driven hepatocyte differentiation of human pluripotent stem cells. Stem Cell Rep 4:939–952. https://doi.org/10.1016/j.stemcr.2015.04.001
Simeonov KP, Uppal H (2014) Direct reprogramming of human fibroblasts to hepatocyte-like cells by synthetic modified mRNAs. PLoS ONE 9:e100134. https://doi.org/10.1371/journal.pone.0100134
Sirenko O, Hesley J, Rusyn I, Cromwell EF (2014) High-content assays for hepatotoxicity using induced pluripotent stem cell-derived cells. Assay Drug Dev Technol 12:43–54. https://doi.org/10.1089/adt.2013.520
Si-Tayeb K, Lemaigre FP, Duncan SA (2010) Organogenesis and development of the liver. Dev Cell 18:175–189. https://doi.org/10.1016/j.devcel.2010.01.011
Snykers S, Vanhaecke T, Papeleu P et al (2006) Sequential exposure to cytokines reflecting embryogenesis: the key for in vitro differentiation of adult bone marrow stem cells into functional hepatocyte-like cells. Toxicol Sci 94:330–341. https://doi.org/10.1093/toxsci/kfl058
Snykers S, De Kock J, Rogiers V, Vanhaecke T (2009) In vitro differentiation of embryonic and adult stem cells into hepatocytes: state of the art. Stem Cells 27:577–605. https://doi.org/10.1634/stemcells.2008-0963
Stock P, Staege MS, Müller LP et al (2008) Hepatocytes derived from adult stem cells. Transplant Proc 40:620–623. https://doi.org/10.1016/j.transproceed.2008.01.058
Subramanian K, Owens DJ, Raju R et al (2014) Spheroid culture for enhanced differentiation of human embryonic stem cells to hepatocyte-like cells. Stem Cells Dev 23:124–131. https://doi.org/10.1089/scd.2013.0097
Suzuki A (2003) Role for growth factors and extracellular matrix in controlling differentiation of prospectively isolated hepatic stem cells. Development 130:2513–2524. https://doi.org/10.1242/dev.00459
Szkolnicka D, Hay DC (2016) Concise review: advances in generating hepatocytes from pluripotent stem cells for translational medicine. Stem Cells 34:1421–1426. https://doi.org/10.1002/stem.2368
Szkolnicka D, Farnworth SL, Lucendo-Villarin B et al (2014) Accurate prediction of drug-induced liver injury using stem cell-derived populations. Stem Cells Transl Med 3:141–148. https://doi.org/10.5966/sctm.2013-0146
Takahashi K, Tanabe K, Ohnuki M et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872. https://doi.org/10.1016/j.cell.2007.11.019
Takayama K, Inamura M, Kawabata K et al (2012) Efficient generation of functional hepatocytes from human embryonic stem cells and induced pluripotent stem cells by HNF4α transduction. Mol Ther 20:127–137. https://doi.org/10.1038/mt.2011.234
Takayama K, Kawabata K, Nagamoto Y et al (2013) 3D spheroid culture of hESC/hiPSC-derived hepatocyte-like cells for drug toxicity testing. Biomaterials 34:1781–1789. https://doi.org/10.1016/j.biomaterials.2012.11.029
Takebe T, Sekine K, Kimura M et al (2017) Massive and reproducible production of liver buds entirely from human pluripotent stem cells. Cell Rep 21:2661–2670. https://doi.org/10.1016/j.celrep.2017.11.005
Talaei-Khozani T, Borhani-haghighi M, Ayatollahi M, Vojdani Z (2015) An in vitro model for hepatocyte-like cell differentiation from Wharton’s jelly derived-mesenchymal stem cells by cell-base aggregates. Gastroenterol Hepatol Bed Bench 8:188–199
Tanimizu N, Miyajima A, Mostov KE (2007) Liver progenitor cells develop cholangiocyte-type epithelial polarity in three-dimensional culture. Mol Biol Cell 18:1472–1479. https://doi.org/10.1091/mbc.E06-09-0848
Tasnim F, Phan D, Toh YC, Yu H (2015) Cost-effective differentiation of hepatocyte-like cells from human pluripotent stem cells using small molecules. Biomaterials 70:115–125. https://doi.org/10.1016/j.biomaterials.2015.08.002
Tasnim F, Toh Y, Qu Y et al (2016) Functionally enhanced human stem cell derived hepatocytes in galactosylated cellulosic sponges for hepatotoxicity testing. Mol Pharm 13:1947–1957. https://doi.org/10.1021/acs.molpharmaceut.6b00119
Teplicky T, Cunderlikova B, Mateasik A et al (2016) Scaffolds fabricated by 3D two-photon photopolymerization for live cell studies. In: 20th Slovak-Czech-Polish optical conference, p 101420C. https://doi.org/10.1117/12.2262966
Treyer A, Müsch A (2013) Hepatocyte polarity. Compr Physiol 3:243–287. https://doi.org/10.1002/cphy.c120009
Tsou YH, Khoneisser J, Huang PC, Xu X (2016) Hydrogel as a bioactive material to regulate stem cell fate. Bioact Mater 1:39–55. https://doi.org/10.1016/j.bioactmat.2016.05.001
Twaroski K, Mallanna SK, Jing R et al (2015) FGF2 mediates hepatic progenitor cell formation during human pluripotent stem cell differentiation by inducing the WNT antagonist NKD1. Genes Dev 29:2463–2474. https://doi.org/10.1101/gad.268961.115
Ullah I, Subbarao RB, Rho GJ (2015) Human mesenchymal stem cells—current trends and future prospective. Biosci Rep 35:e0019. https://doi.org/10.1042/BSR20150025
Ulvestad M, Nordell P, Asplund A et al (2013) Drug metabolizing enzyme and transporter protein profiles of hepatocytes derived from human embryonic and induced pluripotent stem cells. Biochem Pharmacol 86:691–702. https://doi.org/10.1016/j.bcp.2013.06.029
Upadhyay RK (2017) Role of biological scaffolds, hydro gels and stem cells in tissue regeneration therapy. Adv Tissue Eng Regen Med Open Access 2:121–135. https://doi.org/10.15406/atroa.2017.02.00020
Uygun BE, Soto-Gutierrez A, Yagi H et al (2010) Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat Med 16:814–820. https://doi.org/10.1038/nm.2170
Van Hoorick J, Gruber P, Markovic M et al (2017) Cross-linkable gelatins with superior mechanical properties through carboxylic acid modification: increasing the two-photon polymerization potential. Biomacromolecules 18:3260–3272. https://doi.org/10.1021/acs.biomac.7b00905
Van Hoorick J, Gruber P, Markovic M et al (2018) Highly reactive thiol-norbornene photo-click hydrogels: toward improved processability. Macromol Rapid Commun 39:e1800181. https://doi.org/10.1002/marc.201800181
Vishwakarma SK, Bardia A, Lakkireddy C et al (2018) Bioengineered humanized livers as better three-dimensional drug testing model system. World J Hepatol 10:22–33. https://doi.org/10.4254/wjh.v10.i1.22
Wallin P, Zandén C, Carlberg B et al (2012) A method to integrate patterned electrospun fibers with microfluidic systems to generate complex microenvironments for cell culture applications. Biomicrofluidics 6:24131. https://doi.org/10.1063/1.4729747
Wang M, Pei H, Zhang L et al (2010) Hepatogenesis of adipose-derived stem cells on poly-lactide-co-glycolide scaffolds: in vitro and in vivo studies. Tissue Eng Part C Methods 16:1041–1050. https://doi.org/10.1089/ten.tec.2009.0244
Wang J, Zong C, Shi D et al (2012) Hepatogenic engineering from human bone marrow mesenchymal stem cells in porous polylactic glycolic acid scaffolds under perfusion culture. J Tissue Eng Regen Med 6:29–39. https://doi.org/10.1002/term.393
Wang Y, Alhaque S, Cameron K et al (2017) Defined and scalable generation of hepatocyte-like cells from human pluripotent stem cells. J Vis Exp 121:55355. https://doi.org/10.3791/55355
Wang B, Li W, Dean D et al (2018) Enhanced hepatogenic differentiation of bone marrow derived mesenchymal stem cells on liver ECM hydrogel. J Biomed Mater Res Part A 106:829–838. https://doi.org/10.1002/jbm.a.36278
Ware BR, Berger DR, Khetani SR (2015) Prediction of drug-induced liver injury in micropatterned co-cultures containing iPSC-derived human hepatocytes. Toxicol Sci 145:252–262. https://doi.org/10.1093/toxsci/kfv048
Wu J, Chen Q, Liu W et al (2017) Recent advances in microfluidic 3D cellular scaffolds for drug assays. TrAC Trends Anal Chem 87:19–31. https://doi.org/10.1016/j.trac.2016.11.009
Xue G, Han X, Ma X et al (2016) Effect of microenvironment on differentiation of human umbilical cord mesenchymal stem cells into hepatocytes in vitro and in vivo. Biomed Res Int 2016:8916534. https://doi.org/10.1155/2016/8916534
Ye JS, Su XS, Stoltz JF et al (2015) Signalling pathways involved in the process of mesenchymal stem cells differentiating into hepatocytes. Cell Prolif 48:157–165. https://doi.org/10.1111/cpr.12165
Yen M, Wu YY, Liu YS et al (2016) Efficient generation of hepatic cells from mesenchymal stromal cells by an innovative bio-microfluidic cell culture device. Stem Cell Res Ther 7:120. https://doi.org/10.1186/s13287-016-0371-7
Yu J, Su X, Zhu C et al (2015) GFP labeling and hepatic differentiation potential of human placenta-derived mesenchymal stem cells. Cell Physiol Biochem 35:2299–2308. https://doi.org/10.1159/000374033
Zamule SM, Coslo DM, Chen F, Omiecinski CJ (2011) Differentiation of human embryonic stem cells along a hepatic lineage. Chem Biol Interact 190:62–72. https://doi.org/10.1016/j.cbi.2011.01.009
Zhang Y, Xu L, Wang S et al (2014) Concise review: differentiation of human adult stem cells into hepatocyte-like cells in vitro. Int J Stem Cells 7:49–54. https://doi.org/10.15283/ijsc.2014.7.2.49
Zhang J, Wei X, Zeng R et al (2017) Stem cell culture and differentiation in microfluidic devices toward organ-on-a-chip. Futur Sci OA 3:FSO187. https://doi.org/10.4155/fsoa-2016-0091
Zhu M, Lin S, Sun Y et al (2016) Hydrogels functionalized with N-cadherin mimetic peptide enhance osteogenesis of hMSCs by emulating the osteogenic niche. Biomaterials 77:44–52. https://doi.org/10.1016/j.biomaterials.2015.10.072
Zuk PA, Zhu M, Ashjian P, De Ugarte DA et al (2002) Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 13:4279–4295. https://doi.org/10.1091/mbc.e02-02-0105
Acknowledgements
This work was supported by grants from the ‘Chair Mireille Aerens for alternative methods development’, the Research Foundation-Vlaanderen (FWO) (G030217N and 12H2216N) and Leef milieu Brussel (BIM, SUB/2017/BEA/VUB).
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Natale, A., Vanmol, K., Arslan, A. et al. Technological advancements for the development of stem cell-based models for hepatotoxicity testing. Arch Toxicol 93, 1789–1805 (2019). https://doi.org/10.1007/s00204-019-02465-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-019-02465-y