Abstract
Human induced pluripotent stem (hiPS) cells are established following reprogramming of somatic cells from a wide variety of tissues. Given the scarcity of adult human hepatocytes, hiPS-derived hepatocytes would be a valuable source of cells to study differentiation programs, model patient-specific diseases, test drug toxicities, and cell transplantation therapies. Although hiPS-derived hepatocytes are extensively characterized in cell culture assays, testing these cells in animal models is necessary to fully evaluate their differentiation profile and their lack of tumorigenicity. Immunodeficient mouse models harboring liver damage are effective hosts in which xenogeneic hepatocytes can engraft, proliferate, and participate in liver regeneration, thus constituting a stringent test of hepatocyte functionality. The in vivo evaluation of disease-specific hiPS-derived hepatocytes should broaden our understanding of the cellular and molecular processes involved in inherited metabolic liver disease phenotypes. Herein, we detail our methods to test the functions of hiPS-derived hepatocytes in the context of the immunodeficient Rag2-/-IL2Rγc-/-Alb-uPAtg mouse model.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872
Rashid ST, Corbineau S, Hannan N, Marciniak SJ, Miranda E, Alexander G, Huang-Doran I, Griffin J, Ahrlund-Richter L, Skepper J, Semple R, Weber A, Lomas DA, Vallier L (2010) Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J Clin Invest 120:3127–3136
Si-Tayeb K, Noto FK, Nagaoka M, Li J, Battle MA, Duris C, North PE, Dalton S, Duncan SA (2010) Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells. Hepatology 51:297–305
Ghodsizadeh A, Taei A, Totonchi M, Seifinejad A, Gourabi H, Pournasr B, Aghdami N, Malekzadeh R, Almadani N, Salekdeh GH, Baharvand H (2010) Generation of liver disease-specific induced pluripotent stem cells along with efficient differentiation to functional hepatocyte-like cells. Stem Cell Rev 6:622–632
Cayo MA, Cai J, DeLaForest A, Noto FK, Nagaoka M, Clark BS, Collery RF, Si-Tayeb K, Duncan SA (2012) JD induced pluripotent stem cell-derived hepatocytes faithfully recapitulate the pathophysiology of familial hypercholesterolemia. Hepatology 56:2163–2171
Shultz LD, Ishikawa F, Greiner DL (2007) Humanized mice in translational biomedical research. Nat Rev 7:118–130
Legrand N, Ploss A, Balling R, Becker PD, Borsotti C, Brezillon N, Debarry J, de Jong Y, Deng H, Di Santo JP, Eisenbarth S, Eynon E, Flavell RA, Guzman CA, Huntington ND, Kremsdorf D, Manns MP, Manz MG, Mention JJ, Ott M, Rathinam C, Rice CM, Rongvaux A, Stevens S, Spits H, Strick-Marchand H, Takizawa H, van Lent AU, Wang C, Weijer K, Willinger T, Ziegler P (2009) Humanized mice for modeling human infectious disease: challenges, progress, and outlook. Cell Host Microbe 6:5–9
Touboul T, Hannan NR, Corbineau S, Martinez A, Martinet C, Branchereau S, Mainot S, Strick-Marchand H, Pedersen R, Di Santo J, Weber A, Vallier L (2010) Generation of functional hepatocytes from human embryonic stem cells under chemically defined conditions that recapitulate liver development. Hepatology 51:1754–1765
Yusa K, Rashid ST, Strick-Marchand H, Varela I, Liu PQ, Paschon DE, Miranda E, Ordonez A, Hannan NR, Rouhani FJ, Darche S, Alexander G, Marciniak SJ, Fusaki N, Hasegawa M, Holmes MC, Di Santo JP, Lomas DA, Bradley A, Vallier L (2011) Targeted gene correction of alpha1-antitrypsin deficiency in induced pluripotent stem cells. Nature 478:391–394
Liu H, Kim Y, Sharkis S, Marchionni L, Jang YY (2011) In vivo liver regeneration potential of human induced pluripotent stem cells from diverse origins. Sci Transl Med 3:82
Ma X, Duan Y, Tschudy-Seney B, Roll G, Behbahan IS, Ahuja TP, Tolstikov V, Wang C, McGee J, Khoobyari S, Nolta JA, Willenbring H, Zern MA (2013) Highly efficient differentiation of functional hepatocytes from human induced pluripotent stem cells. Stem Cells Transl Med 2:409–419
Huntington ND, Legrand N, Alves NL, Jaron B, Weijer K, Plet A, Corcuff E, Mortier E, Jacques Y, Spits H, Di Santo JP (2009) IL-15 trans-presentation promotes human NK cell development and differentiation in vivo. J Exp Med 206:25–34
Rongvaux A, Takizawa H, Strowig T, Willinger T, Eynon EE, Flavell RA, Manz MG (2013) Human hemato-lymphoid system mice: current use and future potential for medicine. Annu Rev Immunol 31:635–674
Hannan NR, Segeritz CP, Touboul T, Vallier L (2013) Production of hepatocyte-like cells from human pluripotent stem cells. Nat Protoc 8:430–437
Acknowledgements
The authors thank James Di Santo, Anne Weber, and Ludovic Vallier for helpful and stimulating discussions, and the following funding sources for their support: Agence Nationale de la Recherche (ANR programme Emergence), Agence Nationale de Recherches sur le sida et les hépatites virales (ANRS), Institut Pasteur, and Institut National de la Santé et de la Recherche Médicale (INSERM).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media New York
About this protocol
Cite this protocol
Dusséaux, M., Darche, S., Strick-Marchand, H. (2014). Animal Models to Test hiPS-Derived Hepatocytes in the Context of Inherited Metabolic Liver Diseases. In: Christ, B., Oerlecke, J., Stock, P. (eds) Animal Models for Stem Cell Therapy. Methods in Molecular Biology, vol 1213. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-1453-1_8
Download citation
DOI: https://doi.org/10.1007/978-1-4939-1453-1_8
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-1452-4
Online ISBN: 978-1-4939-1453-1
eBook Packages: Springer Protocols