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

Maria Paulina Ordonez; Lawrence S.B. Goldstein

doi:10.1055/s-0032-1329898

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2012; 32(04): 298-306
DOI: 10.1055/s-0032-1329898

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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

Authors

Maria Paulina Ordonez

¹Department of Pediatric Gastroenterology, Hepatology and Nutrition, University of California, La Jolla, San Diego, California
Lawrence S.B. Goldstein

²Department of Cellular and Molecular Medicine, University of California, La Jolla, San Diego, California

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

Full Text

References

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