Using Human-Induced Pluripotent Stem Cells to Model Monogenic Metabolic Disorders of the Liver

Abstract

A crucial problem in liver disease biology and a major obstacle to the development of new therapies is the inability to conduct mechanistic studies of live human hepatocytes. Liver tissue from patients is difficult to obtain and only reveals the disease aftermath, while animal models lack the significant genetic diversity of humans. Monogenic metabolic disorders of the liver are an ideal platform to explore the complex gene–environment interactions and the role of genetic variation in the onset and progression of liver disease. Human induced pluripotent stem cell (hIPSC) technology provides an unprecedented opportunity to generate live cellular models of disease for therapeutic candidate discovery and cell replacement therapy. In this review, we discuss the potential of hIPSC to increase our understanding of human disease with a focus on the current efforts to model metabolic diseases of the liver and to generate suitable populations of human hepatocytes for cell transplantation.

Keywords

human-induced pluripotent stem cells - hepatocyte differentiation - disease modeling - inherited liver metabolic disorders - cell transplantation

• References

• 1 Mayatepek E, Hoffmann B, Meissner T. Inborn errors of carbohydrate metabolism. Best Pract Res Clin Gastroenterol 2010; 24 (5) 607-618
• 2 Bechmann LP, Hannivoort RA, Gerken G, Hotamisligil GS, Trauner M, Canbay A. The interaction of hepatic lipid and glucose metabolism in liver diseases. J Hepatol 2012; 56 (4) 952-964
• 3 Lerapetritou MG, Georgopoulos PG, Roth CM, Androulakis LP. Tissue-level modeling of xenobiotic metabolism in liver: An emerging tool for enabling clinical translational research. Clin Transl Sci 2009; 2 (3) 228-237
• 4 Lanpher B, Brunetti-Pierri N, Lee B. Inborn errors of metabolism: the flux from Mendelian to complex diseases. Nat Rev Genet 2006; 7 (6) 449-460
• 5 Melum E, Franke A, Karlsen TH. Genome-wide association studies—a summary for the clinical gastroenterologist. World J Gastroenterol 2009; 15 (43) 5377-5396
• 6 Weber SL, Segal S, Packman W. Inborn errors of metabolism: psychosocial challenges and proposed family systems model of intervention. Mol Genet Metab 2012; 105 (4) 537-541
• 7 Sokal EM. Liver transplantation for inborn errors of liver metabolism. J Inherit Metab Dis 2006; 29 (2-3) 426-430
• 8 Meyburg J, Hoffmann GF. Liver cell transplantation for the treatment of inborn errors of metabolism. J Inherit Metab Dis 2008; 31: 164-172
• 9 Larter CZ, Yeh MM. Animal models of NASH: getting both pathology and metabolic context right. J Gastroenterol Hepatol 2008; 23 (11) 1635-1648
• 10 van der Worp HB, Howells DW, Sena ES , et al. Can animal models of disease reliably inform human studies?. PLoS Med 2010; 7 (3) e1000245
• 11 Colman A, Dreesen O. Pluripotent stem cells and disease modeling. Cell Stem Cell 2009; 5 (3) 244-247
• 12 Jucker M. The benefits and limitations of animal models for translational research in neurodegenerative diseases. Nat Med 2010; 16 (11) 1210-1214
• 13 Wong PC, Cai H, Borchelt DR, Price DL. Genetically engineered mouse models of neurodegenerative diseases. Nat Neurosci 2002; 5 (7) 633-639
• 14 Dawson TM, Ko HS, Dawson VL. Genetic animal models of Parkinson's disease. Neuron 2010; 66 (5) 646-661
• 15 Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126 (4) 663-676
• 16 Takahashi K, Tanabe K, Ohnuki M , et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131 (5) 861-872
• 17 Park I-H, Zhao R, West JA , et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 2008; 451 (7175) 141-146
• 18 Cohen DE, Melton D. Turning straw into gold: directing cell fate for regenerative medicine. Nat Rev Genet 2011; 12 (4) 243-252
• 19 Gurdon JB, Melton DA. Nuclear reprogramming in cells. Science 2008; 322 (5909) 1811-1815
• 20 Ying QL, Wray J, Nichols J , et al. The ground state of embryonic stem cell self-renewal. Nature 2008; 453 (7194) 519-523
• 21 Blau HM, Brazelton TR, Weimann JM. The evolving concept of a stem cell: entity or function?. Cell 2001; 105 (7) 829-841
• 22 Izpisúa Belmonte JC, Ellis J, Hochedlinger K, Yamanaka S. Induced pluripotent stem cells and reprogramming: seeing the science through the hype. Nat Rev Genet 2009; 10 (12) 878-883
• 23 Robinton DA, Daley GQ. The promise of induced pluripotent stem cells in research and therapy. Nature 2012; 481 (7381) 295-305
• 24 Stadtfeld M, Hochedlinger K. Induced pluripotency: history, mechanisms, and applications. Genes Dev 2010; 24 (20) 2239-2263
• 25 Maherali N, Hochedlinger K. Guidelines and techniques for the generation of induced pluripotent stem cells. Cell Stem Cell 2008; 3 (6) 595-605
• 26 Park I-H, Arora N, Huo H , et al. Disease-specific induced pluripotent stem cells. Cell 2008; 134 (5) 877-886
• 27 Maehr R, Chen S, Snitow M , et al. Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci U S A 2009; 106 (37) 15768-15773
• 28 Mou X, Wu Y, Cao H , et al. Generation of disease-specific induced pluripotent stem cells from patients with different karyotypes of Down syndrome. Stem Cell Res Ther 2012; 3 (2) 14
• 29 Sánchez-Danés A, Richaud-Patin Y, Carballo-Carbajal I , et al. Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease. EMBO Molecular Medicine 2012; 4: 1-16
• 30 Schwartz RE, Trehan K, Andrus L , et al. Modeling hepatitis C virus infection using human induced pluripotent stem cells. Proc Natl Acad Sci U S A 2012; 109 (7) 2544-2548
• 31 Yusa K, Rashid ST, Strick-Marchand H , et al. Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells. Nature 2011; 478 (7369) 391-394
• 32 Fairbanks KD, Tavill AS. Liver disease in alpha 1-antitrypsin deficiency: a review. Am J Gastroenterol 2008; 103 (8) 2136-2141 , quiz 2142
• 33 Fregonese L, Stolk J. Hereditary alpha-1-antitrypsin deficiency and its clinical consequences. Orphanet J Rare Dis 2008; 3: 16
• 34 Perlmutter DH, Brodsky JL, Balistreri WF, Trapnell BC. Molecular pathogenesis of alpha-1-antitrypsin deficiency-associated liver disease: a meeting review. Hepatology 2007; 45 (5) 1313-1323
• 35 Petit I, Kesner NS, Karry R , et al. Induced pluripotent stem cells from hair follicles as a cellular model for neurodevelopmental disorders. Stem Cell Res (Amst) 2012; 8 (1) 134-140
• 36 Yan X, Qin H, Qu C, Tuan RS, Shi S, Huang GT. iPS cells reprogrammed from human mesenchymal-like stem/progenitor cells of dental tissue origin. Stem Cells Dev 2010; 19 (4) 469-480
• 37 Kim K, Doi A, Wen B , et al. Epigenetic memory in induced pluripotent stem cells. Nature 2010; 467 (7313) 285-290
• 38 Nishino K, Toyoda M, Yamazaki-Inoue M , et al. DNA methylation dynamics in human induced pluripotent stem cells over time. PLoS Genet 2011; 7 (5) e1002085
• 39 Saha K, Jaenisch R. Technical challenges in using human induced pluripotent stem cells to model disease. Cell Stem Cell 2009; 5 (6) 584-595
• 40 Kaji K, Norrby K, Paca A, Mileikovsky M, Mohseni P, Woltjen K. Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 2009; 458 (7239) 771-775
• 41 Zhou W, Freed CR. Adenoviral gene delivery can reprogram human fibroblasts to induced pluripotent stem cells. Stem Cells 2009; 27 (11) 2667-2674
• 42 Cheng L, Hansen NF, Zhao L , et al; NISC Comparative Sequencing Program. Low incidence of DNA sequence variation in human induced pluripotent stem cells generated by nonintegrating plasmid expression. Cell Stem Cell 2012; 10 (3) 337-344
• 43 Woltjen K, Michael IP, Mohseni P , et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 2009; 458 (7239) 766-770
• 44 Boulting GL, Kiskinis E, Croft GF , et al. A functionally characterized test set of human induced pluripotent stem cells. Nat Biotechnol 2011; 29 (3) 279-286
• 45 Miura K, Okada Y, Aoi T , et al. Variation in the safety of induced pluripotent stem cell lines. Nat Biotechnol 2009; 27 (8) 743-745
• 46 Urnov FD, Miller JC, Lee Y-L , et al. Highly efficient endogenous human gene correction using designed zinc-finger nucleases. Nature 2005; 435 (7042) 646-651
• 47 Hockemeyer D, Wang H, Kiani S , et al. Genetic engineering of human pluripotent cells using TALE nuclease. Nat Biotechnol 2011; 29 (8) 731-734
• 48 Gonzalez FJ, Nebert DW. Evolution of the P450 gene superfamily: animal-plant 'warfare', molecular drive and human genetic differences in drug oxidation. Trends Genet 1990; 6 (6) 182-186
• 49 Lin JH. Species similarities and differences in pharmacokinetics. Drug Metab Dispos 1995; 23 (10) 1008-1021
• 50 Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med 2005; 352 (21) 2211-2221
• 51 Hamazaki T, Iiboshi Y, Oka M , et al. Hepatic maturation in differentiating embryonic stem cells in vitro. FEBS Lett 2001; 497 (1) 15-19
• 52 Chinzei R, Tanaka Y, Shimizu-Saito K , et al. Embryoid-body cells derived from a mouse embryonic stem cell line show differentiation into functional hepatocytes. Hepatology 2002; 36 (1) 22-29
• 53 Touboul T, Hannan NRF, Corbineau S , et al. Generation of functional hepatocytes from human embryonic stem cells under chemically defined conditions that recapitulate liver development. Hepatology 2010; 51 (5) 1754-1765
• 54 Cai J, Zhao Y, Liu Y , et al. Directed differentiation of human embryonic stem cells into functional hepatic cells. Hepatology 2007; 45 (5) 1229-1239
• 55 Murry CE, Keller G. Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 2008; 132 (4) 661-680
• 56 Irion S, Nostro MC, Kattman SJ, Keller GM. Directed differentiation of pluripotent stem cells: from developmental biology to therapeutic applications. Cold Spring Harb Symp Quant Biol 2008; 73: 101-110
• 57 Behbahan IS, Duan Y, Lam A , et al. New approaches in the differentiation of human embryonic stem cells and induced pluripotent stem cells toward hepatocytes. Stem Cell Rev 2011; 7 (3) 748-759
• 58 Gai H, Nguyen DM, Moon YJ , et al. Generation of murine hepatic lineage cells from induced pluripotent stem cells. Differentiation 2010; 79 (3) 171-181
• 59 Duan Y, Ma X, Zou W , et al. Differentiation and characterization of metabolically functioning hepatocytes from human embryonic stem cells. Stem Cells 2010; 28 (4) 674-686
• 60 Asgari S, Moslem M, Bagheri-Lankarani K , et al. Differentiation and transplantation of human induced pluripotent stem cell-derived hepatocyte-like cells. Stem Cell Rev 2011; Nov 11. [Epub ahead of print]
• 61 D'Amour KA, Agulnick AD, Eliazer S, Kelly OG, Kroon E, Baetge EE. Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat Biotechnol 2005; 23 (12) 1534-1541
• 62 Farzaneh Z, Pournasr B, Ebrahimi M, Aghdami N, Baharvand H. Enhanced functions of human embryonic stem cell-derived hepatocyte-like cells on three-dimensional nanofibrillar surfaces. Stem Cell Rev 2010; 6 (4) 601-610
• 63 Ek M, Söderdahl T, Küppers-Munther B , et al. Expression of drug metabolizing enzymes in hepatocyte-like cells derived from human embryonic stem cells. Biochem Pharmacol 2007; 74 (3) 496-503
• 64 Agarwal S, Holton KL, Lanza R. Efficient differentiation of functional hepatocytes from human embryonic stem cells. Stem Cells 2008; 26 (5) 1117-1127
• 65 Yamada T, Yoshikawa M, Kanda S , et al. In vitro differentiation of embryonic stem cells into hepatocyte-like cells identified by cellular uptake of indocyanine green. Stem Cells 2002; 20 (2) 146-154
• 66 Basma H, Soto-Gutiérrez A, Yannam GR , et al. Differentiation and transplantation of human embryonic stem cell-derived hepatocytes. Gastroenterology 2009; 136 (3) 990-999
• 67 Song Z, Cai J, Liu Y , et al. Efficient generation of hepatocyte-like cells from human induced pluripotent stem cells. Cell Res 2009; 19 (11) 1233-1242
• 68 Sullivan GJ, Hay DC, Park I-H , et al. Generation of functional human hepatic endoderm from human induced pluripotent stem cells. Hepatology 2010; 51 (1) 329-335
• 69 Si-Tayeb K, Noto FK, Nagaoka M , et al. Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells. Hepatology 2010; 51 (1) 297-305
• 70 Sekiya S, Suzuki A. Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors. Nature 2011; 475 (7356) 390-393
• 71 Huang P, He Z, Ji S , et al. Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature 2011; 475 (7356) 386-389
• 72 Willenbring H. A simple code for installing hepatocyte function. Cell Stem Cell 2011; 9 (2) 89-91
• 73 Eggenschwiler R, Loya K, Sgodda M, André F, Cantz T. Hepatic differentiation of murine disease-specific induced pluripotent stem cells allows disease modelling in vitro. Stem Cells Int 2011; 2011 (924782) 1-11
• 74 Grompe M. Liver repopulation for the treatment of metabolic diseases. J Inherit Metab Dis 2001; 24 (2) 231-244
• 75 Perlmutter DH. Autophagic disposal of the aggregation-prone protein that causes liver inflammation and carcinogenesis in α-1-antitrypsin deficiency. Cell Death Differ 2009; 16 (1) 39-45
• 76 Teckman JH, An JK, Blomenkamp K, Schmidt B, Perlmutter D. Mitochondrial autophagy and injury in the liver in alpha 1-antitrypsin deficiency. Am J Physiol Gastrointest Liver Physiol 2004; 286 (5) G851-G862
• 77 Perlmutter DH. The role of autophagy in alpha-1-antitrypsin deficiency: a specific cellular response in genetic diseases associated with aggregation-prone proteins. Autophagy 2006; 2 (4) 258-263
• 78 Rashid ST, Corbineau S, Hannan N , et al. Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J Clin Invest 2010; 120 (9) 3127-3136
• 79 Wilson MH, Coates CJ, George Jr AL. PiggyBac transposon-mediated gene transfer in human cells. Mol Ther 2007; 15 (1) 139-145
• 80 Kim A, Pyykko I. Size matters: versatile use of PiggyBac transposons as a genetic manipulation tool. Mol Cell Biochem 2011; 354 (1-2) 301-309
• 81 Mundy H, Lee PJ. The glycogen storage diseases. Curr Paediatr 2004; 14: 407-413
• 82 Ozen H. Glycogen storage diseases: new perspectives. World J Gastroenterol 2007; 13 (18) 2541-2553
• 83 Chou JY, Jun HS, Mansfield BC. Glycogen storage disease type I and G6Pase-β deficiency: etiology and therapy. Nat Rev Endocrinol 2010; 6 (12) 676-688
• 84 Davis MK, Weinstein DA. Liver transplantation in children with glycogen storage disease: controversies and evaluation of the risk/benefit of this procedure. Pediatr Transplant 2008; 12 (2) 137-145
• 85 Wang DQ, Fiske LM, Carreras CT, Weinstein DA. Natural history of hepatocellular adenoma formation in glycogen storage disease type I. J Pediatr 2011; 159 (3) 442-446
• 86 Di Rocco M, Calevo MG, Taro' M, Melis D, Allegri AE, Parenti G. Hepatocellular adenoma and metabolic balance in patients with type Ia glycogen storage disease. Mol Genet Metab 2008; 93 (4) 398-402
• 87 Heller S, Worona L, Consuelo A. Nutritional therapy for glycogen storage diseases. J Pediatr Gastroenterol Nutr 2008; 47 (Suppl. 01) S15-S21
• 88 Wolfsdorf JI, Crigler Jr JF. Effect of continuous glucose therapy begun in infancy on the long-term clinical course of patients with type I glycogen storage disease. J Pediatr Gastroenterol Nutr 1999; 29 (2) 136-143
• 89 Ghosh A, Allamarvdasht M, Pan C-J , et al. Long-term correction of murine glycogen storage disease type Ia by recombinant adeno-associated virus-1-mediated gene transfer. Gene Ther 2006; 13 (4) 321-329
• 90 Chou JY, Mansfield BC. Gene therapy for type I glycogen storage diseases. Curr Gene Ther 2007; 7 (2) 79-88
• 91 Brunetti-Pierri N, Lee B. Gene therapy for inborn errors of liver metabolism. Mol Genet Metab 2005; 86 (1-2) 13-24
• 92 Dhawan A, Mitry RR, Hughes RD. Hepatocyte transplantation for liver-based metabolic disorders. J Inherit Metab Dis 2006; 29 (2-3) 431-435
• 93 Sjouke B, Kusters DM, Kastelein JJP, Hovingh GK. Familial hypercholesterolemia: present and future management. Curr Cardiol Rep 2011; 13 (6) 527-536
• 94 Fahed AC, Nemer GM. Familial hypercholesterolemia: the lipids or the genes?. Nutr Metab (Lond) 2011; 8 (1) 23
• 95 Soutar AK, Naoumova RP. Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med 2007; 4 (4) 214-225
• 96 Wiegman A, Hutten BA, de Groot E , et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. JAMA 2004; 292 (3) 331-337
• 97 Liu ET. Expression genomics and drug development: towards predictive pharmacology. Brief Funct Genomics Proteomics 2005; 3 (4) 303-321
• 98 Ghodsizadeh A, Taei A, Totonchi M , et al. Generation of liver disease-specific induced pluripotent stem cells along with efficient differentiation to functional hepatocyte-like cells. Stem Cell Rev 2010; 6 (4) 622-632
• 99 Sokal EM, Goldstein D, Ciocca M , et al; End-Stage Liver Disease Working Group. End-stage liver disease and liver transplant: current situation and key issues. J Pediatr Gastroenterol Nutr 2008; 47 (2) 239-246
• 100 Singal AK, Duchini A. Liver transplantation in acute alcoholic hepatitis: Current status and future development. World J Hepatol 2011; 3 (8) 215-218
• 101 Feng S, Si M, Taranto SE , et al. Trends over a decade of pediatric liver transplantation in the United States. Liver Transpl 2006; 12 (4) 578-584
• 102 McDiarmid SV, Goodrich NP, Harper AM, Merion RM. Liver transplantation for status 1: the consequences of good intentions. Liver Transpl 2007; 13 (5) 699-707
• 103 Piscaglia AC, Campanale M, Gasbarrini A, Gasbarrini G. Stem cell-based therapies for liver diseases: state of the art and new perspectives. Stem Cells Int 2010; 2010 (259461) 1-10
• 104 Mizuguchi T, Mitaka T, Katsuramaki T, Hirata K. Hepatocyte transplantation for total liver repopulation. J Hepatobiliary Pancreat Surg 2005; 12 (5) 378-385