Semin Liver Dis 2017; 37(01): 017-027
DOI: 10.1055/s-0036-1597818
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Regenerative Medicine and the Biliary Tree

Thiago M. De Assuncao*
1   Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, Minnesota
2   Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, Minnesota
,
Nidhi Jalan-Sakrikar*
1   Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, Minnesota
2   Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, Minnesota
,
Robert C. Huebert
1   Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, Minnesota
2   Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, Minnesota
3   Center for Cell Signaling in Gastroenterology, Mayo Clinic and Foundation, Rochester, Minnesota
› Author Affiliations
Further Information

Publication History

Publication Date:
15 February 2017 (online)

Abstract

Despite decades of basic research, biliary diseases remain prevalent, highly morbid, and notoriously difficult to treat. We have, however, dramatically increased our understanding of biliary developmental biology, cholangiocyte pathophysiology, and the endogenous mechanisms of biliary regeneration and repair. All of this complex and rapidly evolving knowledge coincides with an explosion of new technological advances in the area of regenerative medicine. New breakthroughs such as induced pluripotent stem cells and organoid culture are increasingly being applied to the biliary system; it is only a matter of time until new regenerative therapeutics for the cholangiopathies are unveiled. In this review, the authors integrate what is known about biliary development, regeneration, and repair, and link these conceptual advances to the technological breakthroughs that are collectively driving the emergence of a new global field in biliary regenerative medicine.

* These authors contributed equally.


 
  • References

  • 1 Forbes SJ, Newsome PN. Liver regeneration - mechanisms and models to clinical application. Nat Rev Gastroenterol Hepatol 2016; 13 (8) 473-485
  • 2 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
  • 3 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
  • 4 Sancho-Bru P, Roelandt P, Narain N , et al. Directed differentiation of murine-induced pluripotent stem cells to functional hepatocyte-like cells. J Hepatol 2011; 54 (1) 98-107
  • 5 Choi SM, Kim Y, Liu H, Chaudhari P, Ye Z, Jang YY. Liver engraftment potential of hepatic cells derived from patient-specific induced pluripotent stem cells. Cell Cycle 2011; 10 (15) 2423-2427
  • 6 Chen YF, Tseng CY, Wang HW, Kuo HC, Yang VW, Lee OK. Rapid generation of mature hepatocyte-like cells from human induced pluripotent stem cells by an efficient three-step protocol. Hepatology 2012; 55 (4) 1193-1203
  • 7 Yu Y, Liu H, Ikeda Y , et al. Hepatocyte-like cells differentiated from human induced pluripotent stem cells: relevance to cellular therapies. Stem Cell Res (Amst) 2012; 9 (3) 196-207
  • 8 Aravalli RN, Cressman EN, Steer CJ. Hepatic differentiation of porcine induced pluripotent stem cells in vitro. Vet J 2012; 194 (3) 369-374
  • 9 Zhu S, Rezvani M, Harbell J , et al. Mouse liver repopulation with hepatocytes generated from human fibroblasts. Nature 2014; 508 (7494): 93-97
  • 10 Szkolnicka D, Farnworth SL, Lucendo-Villarin B, Hay DC. Deriving functional hepatocytes from pluripotent stem cells. Curr Protoc Stem Cell Biol 2014; 30: 1-12
  • 11 Takayama K, Inamura M, Kawabata K , et al. Generation of metabolically functioning hepatocytes from human pluripotent stem cells by FOXA2 and HNF1α transduction. J Hepatol 2012; 57 (3) 628-636
  • 12 Schwartz RE, Fleming HE, Khetani SR, Bhatia SN. Pluripotent stem cell-derived hepatocyte-like cells. Biotechnol Adv 2014; 32 (2) 504-513
  • 13 Cayo MA, Cai J, DeLaForest A , et al. JD induced pluripotent stem cell-derived hepatocytes faithfully recapitulate the pathophysiology of familial hypercholesterolemia. Hepatology 2012; 56 (6) 2163-2171
  • 14 Xu D, Alipio Z, Fink LM , et al. Phenotypic correction of murine hemophilia A using an iPS cell-based therapy. Proc Natl Acad Sci U S A 2009; 106 (3) 808-813
  • 15 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
  • 16 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
  • 17 Huebert RC, Rakela J. Cellular therapy for liver disease. Mayo Clin Proc 2014; 89 (3) 414-424
  • 18 Yu Y, Fisher JE, Lillegard JB, Rodysill B, Amiot B, Nyberg SL. Cell therapies for liver diseases. Liver Transpl 2012; 18 (1) 9-21
  • 19 Subba Rao M, Sasikala M, Nageshwar Reddy D. Thinking outside the liver: induced pluripotent stem cells for hepatic applications. World J Gastroenterol 2013; 19 (22) 3385-3396
  • 20 Dianat N, Dubois-Pot-Schneider H, Steichen C , et al. Generation of functional cholangiocyte-like cells from human pluripotent stem cells and HepaRG cells. Hepatology 2014; 60 (2) 700-714
  • 21 De Assuncao TM, Sun Y, Jalan-Sakrikar N , et al. Development and characterization of human-induced pluripotent stem cell-derived cholangiocytes. Lab Invest 2015; 95 (10) 1218
  • 22 Ogawa M, Ogawa S, Bear CE , et al. Directed differentiation of cholangiocytes from human pluripotent stem cells. Nat Biotechnol 2015; 33 (8) 853-861
  • 23 Sampaziotis F, Cardoso de Brito M, Madrigal P , et al. Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation. Nat Biotechnol 2015; 33 (8) 845-852
  • 24 Strazzabosco M, Fabris L. Development of the bile ducts: essentials for the clinical hepatologist. J Hepatol 2012; 56 (5) 1159-1170
  • 25 Itoh T. Stem/progenitor cells in liver regeneration. Hepatology 2016; 64 (2) 663-668
  • 26 Ghanekar A, Kamath BM. Cholangiocytes derived from induced pluripotent stem cells for disease modeling. Curr Opin Gastroenterol 2016; 32 (3) 210-215
  • 27 Hindley CJ, Cordero-Espinoza L, Huch M. Organoids from adult liver and pancreas: stem cell biology and biomedical utility. Dev Biol 2016; ;S0012-1606(16) 30277-9
  • 28 Tabibian JH, Masyuk AI, Masyuk TV, O'Hara SP, LaRusso NF. Physiology of cholangiocytes. Compr Physiol 2013; 3 (1) 541-565
  • 29 O'Hara SP, Tabibian JH, Splinter PL, LaRusso NF. The dynamic biliary epithelia: molecules, pathways, and disease. J Hepatol 2013; 58 (3) 575-582
  • 30 Lazaridis KN, Strazzabosco M, Larusso NF. The cholangiopathies: disorders of biliary epithelia. Gastroenterology 2004; 127 (5) 1565-1577
  • 31 Halilbasic E, Fuchs C, Hofer H, Paumgartner G, Trauner M. Therapy of primary sclerosing cholangitis--today and tomorrow. Dig Dis 2015; 33 (Suppl. 02) 149-163
  • 32 Carbone M, Ronca V, Bruno S, Invernizzi P, Mells GF. Toward precision medicine in primary biliary cholangitis. Dig Liver Dis 2016; 48 (8) 843-850
  • 33 Mousa HS, Carbone M, Malinverno F, Ronca V, Gershwin ME, Invernizzi P. Novel therapeutics for primary biliary cholangitis: toward a disease-stage-based approach. Autoimmun Rev 2016; 15 (9) 870-876
  • 34 Mikolajczyk AE, Te HS, Chapman AB. Gastrointestinal manifestations of autosomal-dominant polycystic kidney disease. Clin Gastroenterol Hepatol 2016; S1542-3565(16)30364-0
  • 35 Verkade HJ, Bezerra JA, Davenport M , et al. Biliary atresia and other cholestatic childhood diseases: advances and future challenges. J Hepatol 2016; 65 (3) 631-642
  • 36 Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology 2013; 145 (6) 1215-1229
  • 37 Lazaridis KN, LaRusso NF. The cholangiopathies. Mayo Clin Proc 2015; 90 (6) 791-800
  • 38 Nelson TJ, Behfar A, Terzic A. Strategies for therapeutic repair: The “R(3)” regenerative medicine paradigm. Clin Transl Sci 2008; 1 (2) 168-171
  • 39 Atala A. Advances in tissue and organ replacement. Curr Stem Cell Res Ther 2008; 3 (1) 21-31
  • 40 Mavila N, Trecartin A, Spurrier R , et al. Functional human and murine tissue-engineered liver is generated from adult stem/progenitor cells. Stem Cells Transl Med 2016; DOI: 10.5966/sctm.2016-0205.
  • 41 Kørbling M, Estrov Z. Adult stem cells for tissue repair - a new therapeutic concept?. N Engl J Med 2003; 349 (6) 570-582
  • 42 Nicolas CT, Wang Y, Nyberg SL. Cell therapy in chronic liver disease. Curr Opin Gastroenterol 2016; 32 (3) 189-194
  • 43 Surani MA, McLaren A. Stem cells: a new route to rejuvenation. Nature 2006; 443 (7109): 284-285
  • 44 Basu J, Ludlow JW. Exosomes for repair, regeneration and rejuvenation. Expert Opin Biol Ther 2016; 16 (4) 489-506
  • 45 Conboy IM, Conboy MJ, Rebo J. Systemic problems: a perspective on stem cell aging and rejuvenation. Aging (Albany, NY) 2015; 7 (10) 754-765
  • 46 Tremblay KD, Zaret KS. Distinct populations of endoderm cells converge to generate the embryonic liver bud and ventral foregut tissues. Dev Biol 2005; 280 (1) 87-99
  • 47 Gualdi R, Bossard P, Zheng M, Hamada Y, Coleman JR, Zaret KS. Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control. Genes Dev 1996; 10 (13) 1670-1682
  • 48 Jung J, Zheng M, Goldfarb M, Zaret KS. Initiation of mammalian liver development from endoderm by fibroblast growth factors. Science 1999; 284 (5422): 1998-2003
  • 49 Rossi JM, Dunn NR, Hogan BL, Zaret KS. Distinct mesodermal signals, including BMPs from the septum transversum mesenchyme, are required in combination for hepatogenesis from the endoderm. Genes Dev 2001; 15 (15) 1998-2009
  • 50 Serls AE, Doherty S, Parvatiyar P, Wells JM, Deutsch GH. Different thresholds of fibroblast growth factors pattern the ventral foregut into liver and lung. Development 2005; 132 (1) 35-47
  • 51 Goessling W, North TE, Lord AM , et al. APC mutant zebrafish uncover a changing temporal requirement for wnt signaling in liver development. Dev Biol 2008; 320 (1) 161-174
  • 52 Ober EA, Verkade H, Field HA, Stainier DY. Mesodermal Wnt2b signalling positively regulates liver specification. Nature 2006; 442 (7103): 688-691
  • 53 Bort R, Signore M, Tremblay K, Martinez Barbera JP, Zaret KS. Hex homeobox gene controls the transition of the endoderm to a pseudostratified, cell emergent epithelium for liver bud development. Dev Biol 2006; 290 (1) 44-56
  • 54 Margagliotti S, Clotman F, Pierreux CE , et al. The onecut transcription factors HNF-6/OC-1 and OC-2 regulate early liver expansion by controlling hepatoblast migration. Dev Biol 2007; 311 (2) 579-589
  • 55 Sosa-Pineda B, Wigle JT, Oliver G. Hepatocyte migration during liver development requires Prox1. Nat Genet 2000; 25 (3) 254-255
  • 56 Hirose Y, Itoh T, Miyajima A. Hedgehog signal activation coordinates proliferation and differentiation of fetal liver progenitor cells. Exp Cell Res 2009; 315 (15) 2648-2657
  • 57 Zong Y, Stanger BZ. Molecular mechanisms of liver and bile duct development. Wiley Interdiscip Rev Dev Biol 2012; 1 (5) 643-655
  • 58 Kamiya A, Gonzalez FJ. TNF-alpha regulates mouse fetal hepatic maturation induced by oncostatin M and extracellular matrices. Hepatology 2004; 40 (3) 527-536
  • 59 Schmidt C, Bladt F, Goedecke S , et al. Scatter factor/hepatocyte growth factor is essential for liver development. Nature 1995; 373 (6516): 699-702
  • 60 Decaens T, Godard C, de Reyniès A , et al. Stabilization of beta-catenin affects mouse embryonic liver growth and hepatoblast fate. Hepatology 2008; 47 (1) 247-258
  • 61 Clotman F, Jacquemin P, Plumb-Rudewiez N , et al. Control of liver cell fate decision by a gradient of TGF beta signaling modulated by onecut transcription factors. Genes Dev 2005; 19 (16) 1849-1854
  • 62 Zong Y, Panikkar A, Xu J , et al. Notch signaling controls liver development by regulating biliary differentiation. Development 2009; 136 (10) 1727-1739
  • 63 Tchorz JS, Kinter J, Müller M, Tornillo L, Heim MH, Bettler B. Notch2 signaling promotes biliary epithelial cell fate specification and tubulogenesis during bile duct development in mice. Hepatology 2009; 50 (3) 871-879
  • 64 Tanimizu N, Miyajima A. Notch signaling controls hepatoblast differentiation by altering the expression of liver-enriched transcription factors. J Cell Sci 2004; 117 (Pt 15): 3165-3174
  • 65 Yanai M, Tatsumi N, Hasunuma N, Katsu K, Endo F, Yokouchi Y. FGF signaling segregates biliary cell-lineage from chick hepatoblasts cooperatively with BMP4 and ECM components in vitro. Dev Dyn 2008; 237 (5) 1268-1283
  • 66 Hofmann JJ, Zovein AC, Koh H, Radtke F, Weinmaster G, Iruela-Arispe ML. Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome. Development 2010; 137 (23) 4061-4072
  • 67 McDaniell R, Warthen DM, Sanchez-Lara PA , et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet 2006; 79 (1) 169-173
  • 68 McCright B, Lozier J, Gridley T. A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency. Development 2002; 129 (4) 1075-1082
  • 69 Li L, Krantz ID, Deng Y , et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 1997; 16 (3) 243-251
  • 70 Oda T, Elkahloun AG, Pike BL , et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 1997; 16 (3) 235-242
  • 71 Geisler F, Nagl F, Mazur PK , et al. Liver-specific inactivation of Notch2, but not Notch1, compromises intrahepatic bile duct development in mice. Hepatology 2008; 48 (2) 607-616
  • 72 Lorent K, Yeo SY, Oda T , et al. Inhibition of Jagged-mediated Notch signaling disrupts zebrafish biliary development and generates multi-organ defects compatible with an Alagille syndrome phenocopy. Development 2004; 131 (22) 5753-5766
  • 73 Hussain SZ, Sneddon T, Tan X, Micsenyi A, Michalopoulos GK, Monga SP. Wnt impacts growth and differentiation in ex vivo liver development. Exp Cell Res 2004; 292 (1) 157-169
  • 74 Choi TY, Ninov N, Stainier DY, Shin D. Extensive conversion of hepatic biliary epithelial cells to hepatocytes after near total loss of hepatocytes in zebrafish. Gastroenterology 2014; 146 (3) 776-788
  • 75 He J, Lu H, Zou Q, Luo L. Regeneration of liver after extreme hepatocyte loss occurs mainly via biliary transdifferentiation in zebrafish. Gastroenterology 2014; 146 (3) 789-800.e8
  • 76 Zajicek G, Oren R, Weinreb Jr M. The streaming liver. Liver 1985; 5 (6) 293-300
  • 77 Malato Y, Naqvi S, Schürmann N , et al. Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration. J Clin Invest 2011; 121 (12) 4850-4860
  • 78 Español-Suñer R, Carpentier R, Van Hul N , et al. Liver progenitor cells yield functional hepatocytes in response to chronic liver injury in mice. Gastroenterology 2012; 143 (6) 1564-1575.e7
  • 79 Higgins GM, Anderson RM. Experimental pathology of the liver I. Restoration of the liver of the white rat following partial surgical removal. Arch Pathol (Chic) 1931; 12: 186-202
  • 80 Farber E. Similarities in the sequence of early histological changes induced in the liver of the rat by ethionine, 2-acetylamino-fluorene, and 3′-methyl-4-dimethylaminoazobenzene. Cancer Res 1956; 16 (2) 142-148
  • 81 Fausto N. Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology 2004; 39 (6) 1477-1487
  • 82 Duncan AW, Dorrell C, Grompe M. Stem cells and liver regeneration. Gastroenterology 2009; 137 (2) 466-481
  • 83 Preisegger KH, Factor VM, Fuchsbichler A, Stumptner C, Denk H, Thorgeirsson SS. Atypical ductular proliferation and its inhibition by transforming growth factor beta1 in the 3,5-diethoxycarbonyl-1,4-dihydrocollidine mouse model for chronic alcoholic liver disease. Lab Invest 1999; 79 (2) 103-109
  • 84 Akhurst B, Croager EJ, Farley-Roche CA , et al. A modified choline-deficient, ethionine-supplemented diet protocol effectively induces oval cells in mouse liver. Hepatology 2001; 34 (3) 519-522
  • 85 Roskams TA, Theise ND, Balabaud C , et al. Nomenclature of the finer branches of the biliary tree: canals, ductules, and ductular reactions in human livers. Hepatology 2004; 39 (6) 1739-1745
  • 86 Miyajima A, Tanaka M, Itoh T. Stem/progenitor cells in liver development, homeostasis, regeneration, and reprogramming. Cell Stem Cell 2014; 14 (5) 561-574
  • 87 Van Hul NK, Abarca-Quinones J, Sempoux C, Horsmans Y, Leclercq IA. Relation between liver progenitor cell expansion and extracellular matrix deposition in a CDE-induced murine model of chronic liver injury. Hepatology 2009; 49 (5) 1625-1635
  • 88 Lorenzini S, Bird TG, Boulter L , et al. Characterisation of a stereotypical cellular and extracellular adult liver progenitor cell niche in rodents and diseased human liver. Gut 2010; 59 (5) 645-654
  • 89 Kuramitsu K, Sverdlov DY, Liu SB , et al. Failure of fibrotic liver regeneration in mice is linked to a severe fibrogenic response driven by hepatic progenitor cell activation. Am J Pathol 2013; 183 (1) 182-194
  • 90 Hayner NT, Braun L, Yaswen P, Brooks M, Fausto N. Isozyme profiles of oval cells, parenchymal cells, and biliary cells isolated by centrifugal elutriation from normal and preneoplastic livers. Cancer Res 1984; 44 (1) 332-338
  • 91 Yaswen P, Hayner NT, Fausto N. Isolation of oval cells by centrifugal elutriation and comparison with other cell types purified from normal and preneoplastic livers. Cancer Res 1984; 44 (1) 324-331
  • 92 Sirica AE, Mathis GA, Sano N, Elmore LW. Isolation, culture, and transplantation of intrahepatic biliary epithelial cells and oval cells. Pathobiology 1990; 58 (1) 44-64
  • 93 Theise ND, Saxena R, Portmann BC , et al. The canals of Hering and hepatic stem cells in humans. Hepatology 1999; 30 (6) 1425-1433
  • 94 Lanzoni G, Cardinale V, Carpino G. The hepatic, biliary, and pancreatic network of stem/progenitor cell niches in humans: a new reference frame for disease and regeneration. Hepatology 2016; 64 (1) 277-286
  • 95 Wang B, Zhao L, Fish M, Logan CY, Nusse R. Self-renewing diploid Axin2(+) cells fuel homeostatic renewal of the liver. Nature 2015; 524 (7564): 180-185
  • 96 Kopp JL, Grompe M, Sander M. Stem cells versus plasticity in liver and pancreas regeneration. Nat Cell Biol 2016; 18 (3) 238-245
  • 97 Reid LM. Stem/progenitor cells and reprogramming (plasticity) mechanisms in liver, biliary tree, and pancreas. Hepatology 2016; 64 (1) 4-7
  • 98 Huch M, Dollé L. The plastic cellular states of liver cells: are EpCAM and Lgr5 fit for purpose?. Hepatology 2016; 64 (2) 652-662
  • 99 Sackett SD, Li Z, Hurtt R , et al. Foxl1 is a marker of bipotential hepatic progenitor cells in mice. Hepatology 2009; 49 (3) 920-929
  • 100 Furuyama K, Kawaguchi Y, Akiyama H , et al. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet 2011; 43 (1) 34-41
  • 101 Huch M, Dorrell C, Boj SF , et al. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 2013; 494 (7436): 247-250
  • 102 Rodrigo-Torres D, Affò S, Coll M , et al. The biliary epithelium gives rise to liver progenitor cells. Hepatology 2014; 60 (4) 1367-1377
  • 103 Schaub JR, Malato Y, Gormond C, Willenbring H. Evidence against a stem cell origin of new hepatocytes in a common mouse model of chronic liver injury. Cell Reports 2014; 8 (4) 933-939
  • 104 Tarlow BD, Finegold MJ, Grompe M. Clonal tracing of Sox9+ liver progenitors in mouse oval cell injury. Hepatology 2014; 60 (1) 278-289
  • 105 Yanger K, Knigin D, Zong Y , et al. Adult hepatocytes are generated by self-duplication rather than stem cell differentiation. Cell Stem Cell 2014; 15 (3) 340-349
  • 106 Lu WY, Bird TG, Boulter L , et al. Hepatic progenitor cells of biliary origin with liver repopulation capacity. Nat Cell Biol 2015; 17 (8) 971-983
  • 107 Kamimoto K, Kaneko K, Kok CY, Okada H, Miyajima A, Itoh T. Heterogeneity and stochastic growth regulation of biliary epithelial cells dictate dynamic epithelial tissue remodeling. eLife 2016; 5: e15034
  • 108 Lemaigre FP. Determining the fate of hepatic cells by lineage tracing: facts and pitfalls. Hepatology 2015; 61 (6) 2100-2103
  • 109 Reid LM. Paradoxes in studies of liver regeneration: relevance of the parable of the blind men and the elephant. Hepatology 2015; 62 (2) 330-333
  • 110 Takayama K, Mitani S, Nagamoto Y , et al. Laminin 411 and 511 promote the cholangiocyte differentiation of human induced pluripotent stem cells. Biochem Biophys Res Commun 2016; 474 (1) 91-96
  • 111 Clevers H. Modeling development and disease with organoids. Cell 2016; 165 (7) 1586-1597
  • 112 Lancaster MA, Knoblich JA. Organogenesis in a dish: modeling development and disease using organoid technologies. Science 2014; 345 (6194): 1247125
  • 113 Dedhia PH, Bertaux-Skeirik N, Zavros Y, Spence JR. Organoid models of human gastrointestinal development and disease. Gastroenterology 2016; 150 (5) 1098-1112
  • 114 Huch M, Gehart H, van Boxtel R , et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell 2015; 160 (1–2): 299-312
  • 115 Takebe T, Sekine K, Enomura M , et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 2013; 499 (7459): 481-484
  • 116 Michalopoulos GK, Bowen WC, Mulè K, Stolz DB. Histological organization in hepatocyte organoid cultures. Am J Pathol 2001; 159 (5) 1877-1887
  • 117 Shin S, Walton G, Aoki R , et al. Foxl1-Cre-marked adult hepatic progenitors have clonogenic and bilineage differentiation potential. Genes Dev 2011; 25 (11) 1185-1192
  • 118 Tanimizu N, Miyajima A, Mostov KE. Liver progenitor cells develop cholangiocyte-type epithelial polarity in three-dimensional culture. Mol Biol Cell 2007; 18 (4) 1472-1479
  • 119 Kido T, Koui Y, Suzuki K , et al. CPM is a useful cell surface marker to isolate expandable bi-potential liver progenitor cells derived from human iPS cells. Stem Cell Rep 2015; 5 (4) 508-515
  • 120 Lugli N, Kamileri I, Keogh A , et al. R-spondin 1 and noggin facilitate expansion of resident stem cells from non-damaged gallbladders. EMBO Rep 2016; 17 (5) 769-779
  • 121 Yu B, He ZY, You P , et al. Reprogramming fibroblasts into bipotential hepatic stem cells by defined factors. Cell Stem Cell 2013; 13 (3) 328-340