Supporting References 6. Yoon SM, Gerasimidou D, Kuwahara R, Hytiroglou P, Yoo JE, Park YN, et al. Epithelial cell adhesion molecule (EpCAM) marks hepatocytes newly derived from stem/progenitor cells in humans. Hepatology 2011;53:964-973. 7. Zhang L, Theise N, Chua M, Reid LM. The stem cell niche of human livers: symmetry between development and regeneration. Hepatology 2008;48:1598-1607. 8. Crawford AR, Lin XZ, Crawford JM. The normal adult human liver biopsy: a quantitative reference standard. Hepatology 1998;28:323-331. 9. van den Heuvel MC, de Jong KP, Boot M, Slooff MJ, Poppema S, Gouw AS. Preservation of bile ductules mitigates bile duct loss. Am J Transplant 2006;6:2660-2671. 10. van den Heuvel MC, de Jong KP, van der Horst ML, Poppema S, Slooff MJ, Gouw AS. Impaired regeneration of biliary cells in human chronic liver allograft rejection. Special emphasis on the role of the finest branches of the biliary tree. Liver Transpl 2004;10:2835. 11. Alvaro D, Mancino MG, Glaser S, Gaudio E, Marzioni M, Francis H, et al. Proliferating cholangiocytes: a neuroendocrine compartment in the diseased liver. Gastroenterology 2007;132:415-431. 12. Desmet VJ. Ductal plates in hepatic ductular reactions. Hypothesis and implications. III. Implications for liver pathology. Virchows Arch 2011;458:271-279. 13. Turanyi E, Dezso K, Csomor J, Schaff Z, Paku S, Nagy P. Immunohistochemical classification of ductular reactions in human liver. Histopathology 2010;57:607-614. 14. Craig CE, Quaglia A, Selden C, Lowdell M, Hodgson H, Dhillon AP. The histopathology of regeneration in massive hepatic necrosis. Semin Liver Dis 2004;24:49-64. 15. Xiao SY, Lu L, Wang HL. Fibrosing cholestatic hepatitis: clinicopathologic spectrum, diagnosis and pathogenesis. Int J Clin Exp Pathol 2008;1:396-402. 16. Clouston AD, Powell EE, Walsh MJ, Richardson MM, Demetris AJ, Jonsson JR. Fibrosis correlates with a ductular reaction in hepatitis C: roles of impaired replication, progenitor cells and steatosis. Hepatology 2005;41:809-818. 17. Brunt EM, Blomenkamp K, Ahmed M, Ali F, Marcus N, Teckman J. Hepatic progenitor cell proliferation and liver injury in alpha-1-antitrypsin deficiency. J Pediatr Gastroenterol Nutr 2010;51:626-630. 18. Richardson MM, Jonsson JR, Powell EE, Brunt EM, Neuschwander-Tetri BA, Bhathal 1 PS, et al. Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction. Gastroenterology 2007;133:80-90. 19. Bioulac-Sage P, Cubel G, Balabaud C, Zucman-Rossi J. Revisiting the pathology of resected benign hepatocellular nodules using new immunohistochemical markers. Semin Liver Dis 2011;31:91-103. 20. Zhou H, Rogler LE, Teperman L, Morgan G, Rogler CE. Identification of hepatocytic and bile ductular cell lineages and candidate stem cells in bipolar ductular reactions in cirrhotic human liver. Hepatology 2007;45:716-724. 21. Turner R, Lozoya O, Wang Y, Cardinale V, Gaudio E, Alpini G, et al. Human hepatic stem cell and maturational liver lineage biology. Hepatology 2011;53:1035-1045. 22. Spee B, Carpino G, Schotanus BA, Katoonizadeh A, Vander Borght S, Gaudio E, et al. Characterisation of the liver progenitor cell niche in liver diseases: potential involvement of Wnt and Notch signalling. Gut 2010;59:247-257. 23. Van Den Heuvel MC, Slooff MJ, Visser L, Muller M, De Jong KP, Poppema S, et al. Expression of anti-OV6 antibody and anti-N-CAM antibody along the biliary line of normal and diseased human livers. Hepatology 2001;33:1387-1393. 24. Desmet VJ. Ductal plates in hepatic ductular reactions. Hypothesis and implications. I. Types of ductular reaction reconsidered. Virchows Arch 2011;458:251-259. 25. Theise ND. Gastrointestinal stem cells. III. Emergent themes of liver stem cell biology: niche, quiescence, self-renewal, and plasticity. Am J Physiol Gastrointest Liver Physiol 2006;290:G189-G193. 26. Wang Y, Yao HL, Cui CB, Wauthier E, Barbier C, Costello MJ, et al. Paracrine signals from mesenchymal cell populations govern the expansion and differentiation of human hepatic stem cells to adult liver fates. Hepatology 2010;52:1443-1454. 27. Lorenzini S, Bird TG, Boulter L, Bellamy C, Samuel K, Aucott R, et al. Characterisation of a stereotypical cellular and extracellular adult liver progenitor cell niche in rodents and diseased human liver. Gut 2010;59:645-654. 28. Gouw AS, van den Heuvel MC, Boot M, Slooff MJ, Poppema S, de Jong KP. Dynamics of the vascular profile of the finer branches of the biliary tree in normal and diseased human livers. J Hepatol 2006;45:393-400. 29. Petersen B, Shupe T. Location is everything: the liver stem cell niche. Hepatology 2008;47:1810-1812. 30. Fellous TG, Islam S, Tadrous PJ, Elia G, Kocher HM, Bhattacharya S, et al. Locating the stem cell niche and tracing hepatocyte lineages in human liver. Hepatology 2009;49:16552 1663. 31. Kuwahara R, Kofman AV, Landis CS, Swenson ES, Barendswaard E, Theise ND. The hepatic stem cell niche: identification by label-retaining cell assay. Hepatology 2008;47:1994-2002. 32. Schmelzer E, Zhang L, Bruce A, Wauthier E, Ludlow J, Yao HL, et al. Human hepatic stem cells from fetal and postnatal donors. J Exp Med 2007;204:1973-1987. 33. Haque S, Haruna Y, Saito K, Nalesnik MA, Atillasoy E, Thung SN, et al. Identification of bipotential progenitor cells in human liver regeneration. Lab Invest 1996;75:699-705. 34. Oh SH, Witek RP, Bae SH, Zheng D, Jung Y, Piscaglia AC, et al. Bone marrow-derived hepatic oval cells differentiate into hepatocytes in 2-acetylaminofluorene/partial hepatectomy-induced liver regeneration. Gastroenterology 2007;132:1077-1087. 35. Theise ND, Nimmakayalu M, Gardner R, Illei PB, Morgan G, Teperman L, et al. Liver from bone marrow in humans. Hepatology 2000;32:11-16. 36. Diaz R, Kim JW, Hui JJ, Li Z, Swain GP, Fong KS, et al. Evidence for the epithelial to mesenchymal transition in biliary atresia fibrosis. Hum Pathol 2008;39:102-115. 37. Lunz JG, Specht S, Isse K, Clouston A, Demetris AJ. Ductular reactions during the development of cirrhosis. In: De Morrow S, Marzioni M, Fava G, Glaser S, Alpini G, editors. Pathophysiology of the Intrahepatic Biliary Epithelium. Kerala, India: Transworld Research Network; 2008:223-256. 38. Jakubowski A, Ambrose C, Parr M, Lincecum JM, Wang MZ, Zheng TS, et al. TWEAK induces liver progenitor cell proliferation. J Clin Invest 2005;115:2330-2340. 39. Viebahn CS, Benseler V, Holz LE, Elsegood CL, Vo M, Bertolino P, et al. Invading macrophages play a major role in the liver progenitor cell response to chronic liver injury. J Hepatol 2010;53:500-507. 40. Sicklick JK, Li YX, Melhem A, Schmelzer E, Zdanowicz M, Huang J, et al. Hedgehog signaling maintains resident hepatic progenitors throughout life. Am J Physiol Gastrointest Liver Physiol 2006;290:G859-G870. 41. Riehle KJ, Dan YY, Campbell JS, Fausto N. New concepts in liver regeneration. J Gastroenterol Hepatol 2011;26(suppl 1):203-212. 42. Kotoula V, Hytiroglou P, Pyrpasopoulou A, Saxena R, Thung SN, Papadimitriou CS. Expression of human telomerase reverse transcriptase in regenerative and precancerous lesions of cirrhotic livers. Liver 2002;22:57-69. 43. Lunz JG 3rd, Tsuji H, Nozaki I, Murase N, Demetris AJ. An inhibitor of cyclin-dependent kinase, stress-induced p21Waf-1/Cip-1, mediates hepatocyte mito-inhibition during the 3 evolution of cirrhosis. Hepatology 2005;41:1262-1271. 44. Menthena A, Koehler CI, Sandhu JS, Yovchev MI, Hurston E, Shafritz DA, et al. Activin A, p15INK4b signaling, and cell competition promote stem/progenitor cell repopulation of livers in aging rats. Gastroenterology 2011;140:1009-1020. 45. Furrer K, Rickenbacher A, Tian Y, Jochum W, Bittermann AG, Kach A, et al. Serotonin reverts age-related capillarization and failure of regeneration in the liver through a VEGFdependent pathway. Proc Natl Acad Sci U S A 2011;108:2945-2950. 46. Delladetsima J, Alexandrou P, Giaslakiotis K, Psichogiou M, Hatzis G, Sypsa V, et al. Hepatic progenitor cells in chronic hepatitis C: a phenomenon of older age and advanced liver disease. Virchows Arch 2010;457:457-466. 47. Cassiman D, Libbrecht L, Sinelli N, Desmet V, Denef C, Roskams T. The vagal nerve stimulates activation of the hepatic progenitor cell compartment via muscarinic acetylcholine receptor type 3. Am J Pathol 2002;161:521-530. 48. Huang W, Ma K, Zhang J, Qatanani M, Cuvillier J, Liu J, et al. Nuclear receptordependent bile acid signaling is required for normal liver regeneration. Science 2006;312:233-236. 49. Apte U, Thompson MD, Cui S, Liu B, Cieply B, Monga SP. Wnt/beta-catenin signaling mediates oval cell response in rodents. Hepatology 2008;47:288-295. 50. Tirnitz-Parker JE, Viebahn CS, Jakubowski A, Klopcic BR, Olynyk JK, Yeoh GC, et al. Tumor necrosis factor-like weak inducer of apoptosis is a mitogen for liver progenitor cells. Hepatology 2010;52:291-302. 51. Sparks EE, Huppert KA, Brown MA, Washington MK, Huppert SS. Notch signaling regulates formation of the three-dimensional architecture of intrahepatic bile ducts in mice. Hepatology 2010;51:1391-1400. 52. Cowley AW Jr. The elusive field of systems biology. Physiol Genomics 2004;16:285-286. 53. Theise ND. Liver stem cells: the fall and rise of tissue biology. Hepatology 2003;38:804806. 54. Theise ND. Stem cell plasticity: recapping the decade, mapping the future. Exp Hematol 2010;38:529-539. 55. D'Inverno M, Theise ND, Prophet J. Mathematical modeling of stem cells: A complexity primer for the stem cell biologist. In: Potten C, Wilson J, Clarke R, Renahan A, eds. Tissue Stem Cells: Biology and Applications. 2nd ed. New York, NY: Marcel Dekker; 2006. 56. Theise ND. Now you see it, now you don't. Nature 2005;435:1165. 4 57. Theise ND. Implications of 'postmodern biology' for pathology: the cell doctrine. Lab Invest 2006;86:335-344. 58. Hoehme S, Brulport M, Bauer A, Bedawy E, Schormann W, Hermes M, et al. Prediction and validation of cell alignment along microvessels as order principle to restore tissue architecture in liver regeneration. Proc Natl Acad Sci U S A 2010;107:10371-10376. 59. Roeder I. Quantitative stem cell biology: computational studies in the hematopoietic system. Curr Opin Hematol 2006;13:222-228. 60. Rojkind M, Philips G, Diehl AM. Microarchitecture of the liver: a jigsaw puzzle. J Hepatol 2011;54:187-188. 61. Odum EP, Barrett GW. Fundamentals of Ecology. 5th ed. Belmont, CA: Cengage Learning; 2004. 62. Futuyma D. Evolutionary Biology. 3rd ed. Sunderland, MA: Sinauer Associates; 1998. 63. Powell EE, Jonsson JR, Clouston AD. Steatosis: co-factor in other liver diseases. Hepatology 2005;42:5-13. 64. Clouston AD, Jonsson JR, Powell EE. Hepatic progenitor cell-mediated regeneration and fibrosis: chicken or egg? Hepatology 2009;49:1424-1426. 65. Van Hul NK, Abarca-Quinones J, Sempoux C, Horsmans Y, Leclercq IA. Relation between liver progenitor cell expansion and extracellular matrix deposition in a CDEinduced murine model of chronic liver injury. Hepatology 2009;49:1625-1635. 66. Svegliati-Baroni G, Faraci G, Fabris L, Saccomanno S, Cadamuro M, Pierantonelli I, et al. Insulin resistance and necroinflammation drives ductular reaction and epithelialmesenchymal transition in chronic hepatitis C. Gut 2011;60:108-115. 67. Fabris L, Cadamuro M, Guido M, Spirli C, Fiorotto R, Colledan M, et al. Analysis of liver repair mechanisms in Alagille syndrome and biliary atresia reveals a role for notch signaling. Am J Pathol 2007;171:641-653. 68. Ryan MJ, Bales C, Nelson A, Gonzalez DM, Underkoffler L, Segalov M, et al. Bile duct proliferation in Jag1/fringe heterozygous mice identifies candidate modifiers of the Alagille syndrome hepatic phenotype. Hepatology 2008;48:1989-1997. 69. Choi SS, Diehl AM. Epithelial-to-mesenchymal transitions in the liver. Hepatology 2009;50:2007-2013. 70. Wells RG. The epithelial-to-mesenchymal transition in liver fibrosis: here today, gone tomorrow? Hepatology 2010;51:737-740. 71. Taura K, Miura K, Iwaisako K, Osterreicher CH, Kodama Y, Penz-Osterreicher M, et al. Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice. 5 Hepatology 2010;51:1027-1036. 72. Rygiel KA, Robertson H, Marshall HL, Pekalski M, Zhao L, Booth TA, et al. Epithelialmesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease. Lab Invest 2008;88:112-123. 73. Ziol M, Nault JC, Aout M, Barget N, Tepper M, Martin A, et al. Intermediate hepatobiliary cells predict an increased risk of hepatocarcinogenesis in patients with hepatitis C virus-related cirrhosis. Gastroenterology 2010;139:335-343 e2. 74. Yamashita T, Forgues M, Wang W, Kim JW, Ye Q, Jia H, et al. EpCAM and alphafetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res 2008;68:1451-1461. 75. Komuta M, Spee B, Vander Borght S, De Vos R, Verslype C, Aerts R, et al. Clinicopathological study on cholangiolocellular carcinoma suggesting hepatic progenitor cell origin. Hepatology 2008;47:1544-1556. 76. Lee JS, Heo J, Libbrecht L, Chu IS, Kaposi-Novak P, Calvisi DF, et al. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med 2006;12:410-416. 77. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646674. 78. Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY, et al. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology 2009;136:1012-1024. 79. Ikeda H, Sasaki M, Sato Y, Harada K, Zen Y, Mitsui T, et al. Bile ductular cell reaction with senescent hepatocytes in chronic viral hepatitis is lost during hepatocarcinogenesis. Pathol Int 2009;59:471-478. 80. Lennerz JK, Chapman WC, Brunt EM. Keratin 19 epithelial patterns in cirrhotic stroma parallel hepatocarcinogenesis. Am J Pathol 2011;179:1015-1029. 6