Future Therapeutic Approaches for Alagille Syndrome

  • Emma R. AnderssonEmail author


Disease phenomena in Alagille syndrome range from bile duct paucity to cardiac defects, kidney disease, and bone weakness. Current treatments focus on ensuring nutrition and managing symptoms such as pruritus and in some cases liver and/or heart transplantation. In this chapter, future potential therapies or cures for Alagille syndrome are discussed, as well as state-of-the-art systems for drug discovery.

Future potential strategies range from treatment of disease outcomes (replacing and/or repairing missing cells or organs with stem cells or bioengineered organs) to directly correcting the underlying Notch pathway dysregulation to ensure proper development of the organs to begin with (correcting hypomorphic Notch signaling). Drawing on recent advances in the field, this chapter describes Notch activation or inhibition peptides, gene manipulation techniques, advances in stem cell biology, and our improved understanding of endogenous reparative mechanisms. These putative therapeutic possibilities hold great potential for Alagille syndrome and are also highly translatable to other disease states in which the liver or heart is compromised.


Jagged1 Stem cells Induced pluripotent stem cells/iPSCs CRISPR/Cas9 Organ on a chip Reparative medicine Regenerative medicine 


Conflict of Interest

ER Andersson has a project funded by Moderna Therapeutics. The funder had no role or influence in the writing of this chapter.


  1. 1.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.PubMedGoogle Scholar
  2. 2.
    Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K. Induced pluripotent stem cells generated without viral integration. Science. 2008;322(5903):945–9.PubMedPubMedCentralGoogle Scholar
  3. 3.
    FUSAKI N, BAN H, NISHIYAMA A, SAEKI K, HASEGAWA M. Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proc Japan Acad Ser B. 2009;85(8):348–62.Google Scholar
  4. 4.
    Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S. Generation of mouse induced pluripotent stem cells without viral vectors. Science. 2008;322(5903):949–53.PubMedGoogle Scholar
  5. 5.
    Warren L, Manos PD, Ahfeldt T, Loh Y-H, Li H, Lau F, et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell. 2010;7(5):618–30.PubMedPubMedCentralGoogle Scholar
  6. 6.
    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):771–5.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Yusa K, Rad R, Takeda J, Bradley A. Generation of transgene-free induced pluripotent mouse stem cells by the piggyBac transposon. Nat Methods. 2009;6(5):363–9.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Woltjen K, Michael IP, Mohseni P, Desai R, Mileikovsky M, Hämäläinen R, et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature. 2009;458(7239):766–70.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Hou P, Li Y, Zhang X, Liu C, Guan J, Li H, et al. Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science. 2013;341(6146):651–4.PubMedGoogle Scholar
  10. 10.
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.PubMedGoogle Scholar
  11. 11.
    Aasen T, Raya A, Barrero MJ, Garreta E, Consiglio A, Gonzalez F, et al. Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol. 2008;26(11):1276–84.PubMedGoogle Scholar
  12. 12.
    Maherali N, Ahfeldt T, Rigamonti A, Utikal J, Cowan C, Hochedlinger K. A high-efficiency system for the generation and study of human induced pluripotent stem cells. Cell Stem Cell. 2008;3(3):340–5.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Staerk J, Dawlaty MM, Gao Q, Maetzel D, Hanna J, Sommer CA, et al. Reprogramming of human peripheral blood cells to induced pluripotent stem cells. Cell Stem Cell. 2010;7(1):20–4.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Zhou T, Benda C, Dunzinger S, Huang Y, Ho JC, Yang J, et al. Generation of human induced pluripotent stem cells from urine samples. Nat Protoc. 2012;7(12):2080–9.PubMedGoogle Scholar
  15. 15.
    Polo JM, Liu S, Figueroa ME, Kulalert W, Eminli S, Tan KY, et al. Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nat Biotechnol. 2010;28(8):848–55.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Saini N, Roberts SA, Klimczak LJ, Chan K, Grimm SA, Dai S, et al. The Impact of Environmental and Endogenous Damage on Somatic Mutation Load in Human Skin Fibroblasts. Taylor M, editor. PLOS Genet. 2016;12(10):e1006385.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Peterson SE, Loring JF. Genomic instability in pluripotent stem cells: implications for clinical applications. J Biol Chem. 2014;289(8):4578–84.PubMedGoogle Scholar
  18. 18.
    Loukogeorgakis SP, De Coppi P. Concise review: amniotic fluid stem cells: the known, the unknown, and potential regenerative medicine applications. Stem Cells. 2017;35(7):1663–73.PubMedGoogle Scholar
  19. 19.
    De Coppi P, Bartsch G, Siddiqui MM, Xu T, Santos CC, Perin L, et al. Isolation of amniotic stem cell lines with potential for therapy. Nat Biotechnol. 2007;25(1):100–6.PubMedGoogle Scholar
  20. 20.
    Velasquez-Mao AJ, Tsao CJM, Monroe MN, Legras X, Bissig-Choisat B, Bissig K-D, et al. Differentiation of spontaneously contracting cardiomyocytes from non-virally reprogrammed human amniotic fluid stem cells. Cooney AJ, editor. PLoS One. 2017;12(5):e0177824.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Moschidou D, Mukherjee S, Blundell MP, Jones GN, Atala AJ, Thrasher AJ, et al. Human mid-trimester amniotic fluid stem cells cultured under embryonic stem cell conditions with valproic acid acquire pluripotent characteristics. Stem Cells Dev. 2013;22(3):444–58.PubMedGoogle Scholar
  22. 22.
    Davis JW. Skin transplantation with a review of 550 cases at the Johns Hopkins Hospital. Johns Hopkins Med J. 1910;15:307–10.Google Scholar
  23. 23.
    Strom SC, Gramignoli R. Human amnion epithelial cells expressing HLA-G as novel cell-based treatment for liver disease. Hum Immunol. 2016;77(9):734–9.PubMedGoogle Scholar
  24. 24.
    Akle CA, Adinolfi M, Welsh KI, Leibowitz S, McColl I. Immunogenicity of human amniotic epithelial cells after transplantation into volunteers. Lancet. 1981;2(8254):1003–5.PubMedGoogle Scholar
  25. 25.
    Marongiu M, Serra MP, Contini A, Sini M, Strom SC, Laconi E, et al. Rat-derived amniotic epithelial cells differentiate into mature hepatocytes in vivo with no evidence of cell fusion. Stem Cells Dev. 2015;24(12):1429–35.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Gluckman E, Broxmeyer HE, Auerbach AD, et al. Hematopoietic reconstitution in a patient with Fanconi’s animia by means of umbilical cord blood from an HLA-identical sibling. N Engl J Med. 1989;312(17):1174–8.Google Scholar
  27. 27.
    Munoz J, Shah N, Rezvani K, Hosing C, Bollard CM, Oran B, et al. Concise review: umbilical cord blood transplantation: past, present, and future. Stem Cells Transl Med. 2014;3(12):1435–43.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Armitage S. Cord blood banking standards: autologous versus altruistic. Front Med. 2016;2:94.Google Scholar
  29. 29.
    McDonald CA, Fahey MC, Jenkin G, Miller SL. Umbilical cord blood cells for treatment of cerebral palsy; timing and treatment options. Pediatr Res. 2018;83(1–2):333–44.PubMedGoogle Scholar
  30. 30.
    Haase A, Olmer R, Schwanke K, Wunderlich S, Merkert S, Hess C, et al. Generation of induced pluripotent stem cells from human cord blood. Cell Stem Cell. 2009;5(4):434–41.PubMedGoogle Scholar
  31. 31.
    Giorgetti A, Montserrat N, Aasen T, Gonzalez F, Rodríguez-Pizà I, Vassena R, et al. Generation of induced pluripotent stem cells from human cord blood using OCT4 and SOX2. Cell Stem Cell. 2009;5(4):353–7.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Ferraro F, Celso CL, Scadden D. Adult stem cels and their niches. Adv Exp Med Biol. 2010;695:155–68.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Eschenhagen T, Bolli R, Braun T, Field LJ, Fleischmann BK, Frisén J, et al. Cardiomyocyte regeneration: a consensus statement. Circulation. 2017;136(7):680–6.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Hindley CJ, Cordero-Espinoza L, Huch M. Organoids from adult liver and pancreas: stem cell biology and biomedical utility. Dev Biol. 2016;420(2):251–61.PubMedGoogle Scholar
  35. 35.
    Ridola L, Bragazzi MC, Cardinale V, Carpino G, Gaudio E, Alvaro D. Cholangiocytes: cell transplantation. Biochim Biophys Acta - Mol Basis Dis. 2017;1864:1516–23.Google Scholar
  36. 36.
    Michalopoulos GK. Hepatostat: liver regeneration and normal liver tissue maintenance. Hepatology. 2017;65(4):1384–92.PubMedGoogle Scholar
  37. 37.
    Michalopoulos GK, DeFrances MC. Liver regeneration. Science. 1997;276(5309):60–6.PubMedGoogle Scholar
  38. 38.
    Huch M, Dorrell C, Boj SF, van Es JH, Li VSW, van de Wetering M, et al. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature. 2013;494(7436):247–50.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Furuyama K, Kawaguchi Y, Akiyama H, Horiguchi M, Kodama S, Kuhara T, 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.PubMedGoogle Scholar
  40. 40.
    Shin S, Walton G, Aoki R, Brondell K, Schug J, Fox A, et al. Foxl1-Cre-marked adult hepatic progenitors have clonogenic and bilineage differentiation potential. Genes Dev. 2011;25(11):1185–92.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Dorrell C, Erker L, Schug J, Kopp JL, Canaday PS, Fox AJ, et al. Prospective isolation of a bipotential clonogenic liver progenitor cell in adult mice. Genes Dev. 2011;25(11):1193–203.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Yanger K, Knigin D, Zong Y, Maggs L, Gu G, Akiyama H, et al. Adult hepatocytes are generated by self-duplication rather than stem cell differentiation. Cell Stem Cell. 2014;15(3):340–9.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Cao W, Chen K, Bolkestein M, Yin Y, Verstegen MMA, Bijvelds MJC, et al. Dynamics of proliferative and quiescent stem cells in liver homeostasis and injury. Gastroenterology. 2017;153(4):1133–47.PubMedGoogle Scholar
  44. 44.
    Xia T, Liu W, Yang L. A review of gradient stiffness hydrogels used in tissue engineering and regenerative medicine. J Biomed Mater Res Part A. 2017;105(6):1799–812.Google Scholar
  45. 45.
    Caliari SR, Burdick JA. A practical guide to hydrogels for cell culture. Nat Methods. 2016;13(5):405–14.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Lauschke VM, Hendriks DFG, Bell CC, Andersson TB, Ingelman-Sundberg M. Novel 3D culture Systems for Studies of human liver function and assessments of the hepatotoxicity of drugs and drug candidates. Chem Res Toxicol. 2016;29(12):1936–55.PubMedGoogle Scholar
  47. 47.
    Huch M, Gehart H, Van Boxtel R, Hamer K, Blokzijl F, Verstegen MMA, et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell. 2015;160(1–2):299–312.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009;459(7244):262–5.Google Scholar
  49. 49.
    Camp JG, Sekine K, Gerber T, Loeffler-Wirth H, Binder H, Gac M, et al. Multilineage communication regulates human liver bud development from pluripotency. Nature. 2017;546(7659):533–8.PubMedGoogle Scholar
  50. 50.
    Mills RJ, Titmarsh DM, Koenig X, Parker BL, Ryall JG, Quaife-Ryan GA, et al. Functional screening in human cardiac organoids reveals a metabolic mechanism for cardiomyocyte cell cycle arrest. Proc Natl Acad Sci. 2017;114(40):E8372–81.PubMedGoogle Scholar
  51. 51.
    Wang S, Gao D, Chen Y. The potential of organoids in urological cancer research. Nat Rev Urol. 2017;14(7):401–14.PubMedPubMedCentralGoogle Scholar
  52. 52.
    McCright B, Lozier J, Gridley T. A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency. Development. 2002;129(4):1075–82.Google Scholar
  53. 53.
    Vrijens K, Thys S, De Jeu MT, Postnov AA, Pfister M, Cox L, et al. Ozzy, a Jag1 vestibular mouse mutant, displays characteristics of Alagille syndrome. Neurobiol Dis. 2006;24(1):28–40.PubMedGoogle Scholar
  54. 54.
    Underkoffler LA, Carr E, Nelson A, Ryan MJ, Schultz R, Loomes KM. Microarray data reveal relationship between Jag1 and Ddr1 in mouse liver. Kirchmair R, editor. PLoS One. 2013;8(12):e84383.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Lozier J, McCright B, Gridley T. Notch signaling regulates bile duct morphogenesis in mice. PLoS One. 2008;3(3):e1851.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Golson ML, Loomes KM, Oakey R, Kaestner KH. Ductal Malformation and Pancreatitis in Mice Caused by Conditional Jag1 Deletion. Gastroenterology. 2009;136(5):1761–1771.e1.PubMedGoogle Scholar
  57. 57.
    Loomes KM, Russo P, Ryan M, Nelson A, Underkoffler L, Glover C, et al. Bile duct proliferation in liver-specific Jag1 conditional knockout mice: effects of gene dosage. Hepatology. 2007;45(2):323–30.Google Scholar
  58. 58.
    Hofmann JJ, Zovein AC, Koh H, Radtke F, Weinmaster G, Iruela-Arispe ML, et al. Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome. Development. 2010;137(23):4061–72.PubMedPubMedCentralGoogle Scholar
  59. 59.
    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(4):1391–400.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Youngstrom DW, Dishowitz MI, Bales CB, Carr E, Mutyaba PL, Kozloff KM, et al. Jagged1 expression by osteoblast-lineage cells regulates trabecular bone mass and periosteal expansion in mice. Bone. 2016;91:64–74.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Andersson ER, Chivukula IV, Hankeova S, Sjöqvist M, Tsoi YL, Ramsköld D, Masek J, Elmansuri A, Hoogendoorn A, Vazquez E, Storvall H, Netušilová J, Huch M, Fischler B, Ellis E, Contreras A, Nemeth A, Chien KC, Clevers H, Sandberg R, Bryja V, Lendahl U. Mouse Model of Alagille Syndrome and Mechanisms of Jagged1 Missense Mutations. Gastroenterology. 2018;154(4):1080–95.PubMedGoogle Scholar
  62. 62.
    Lorent K, Yeo S-Y, Oda T, Chandrasekharappa S, Chitnis A, Matthews RP, 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):5753–66.PubMedGoogle Scholar
  63. 63.
    Zhang D, Gates KP, Barske L, Wang G, Lancman JJ, Zeng X-XI, et al. Endoderm Jagged induces liver and pancreas duct lineage in zebrafish. Nat Commun. 2017;8(1):769.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Martignoni M, Groothuis GMM, de Kanter R. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol. 2006;2(6):875–94.PubMedGoogle Scholar
  65. 65.
    Lee-Rueckert M, Escola-Gil JC, Kovanen PT. HDL functionality in reverse cholesterol transport — challenges in translating data emerging from mouse models to human disease. Biochim Biophys Acta Mol Cell Biol Lipids. 2016;1861(7):566–83.Google Scholar
  66. 66.
    Xu D, Peltz G. Can humanized mice predict drug “behavior” in humans? Annu Rev Pharmacol Toxicol. 2016;56(1):323–38.PubMedGoogle Scholar
  67. 67.
    Ware BR, Khetani SR. Engineered liver platforms for different phases of drug development. Trends Biotechnol. 2017;35(2):172–83.PubMedGoogle Scholar
  68. 68.
    Sivaraman A, Leach J, Townsend S, Iida T, Hogan B, Stolz D, et al. A microscale in vitro physiological model of the liver: predictive screens for drug metabolism and enzyme induction. Curr Drug Metab. 2005;6(6):569–91.PubMedGoogle Scholar
  69. 69.
    Kasuya J, Sudo R, Mitaka T, Ikeda M, Tanishita K. Spatio-temporal control of hepatic stellate cell–endothelial cell interactions for reconstruction of liver sinusoids In Vitro. Tissue Eng Part A. 2012;18(9–10):1045–56.PubMedGoogle Scholar
  70. 70.
    Kang YBA, Sodunke TR, Lamontagne J, Cirillo J, Rajiv C, Bouchard MJ, et al. Liver sinusoid on a chip: long-term layered co-culture of primary rat hepatocytes and endothelial cells in microfluidic platforms. Biotechnol Bioeng. 2015;112(12):2571–82.PubMedGoogle Scholar
  71. 71.
    Rennert K, Steinborn S, Gröger M, Ungerböck B, Jank A-M, Ehgartner J, et al. A microfluidically perfused three dimensional human liver model. Biomaterials. 2015;71:119–31.PubMedGoogle Scholar
  72. 72.
    Toh Y-C, Lim TC, Tai D, Xiao G, van Noort D, Yu H. A microfluidic 3D hepatocyte chip for drug toxicity testing. Lab Chip. 2009;9(14):2026–35.PubMedGoogle Scholar
  73. 73.
    Shih M-C, Tseng S-H, Weng Y-S, Chu I-M, Liu C-H. A microfluidic device mimicking acinar concentration gradients across the liver acinus. Biomed Microdevices. 2013;15(5):767–80.PubMedGoogle Scholar
  74. 74.
    Burke ZD, Reed KR, Phesse TJ, Sansom OJ, Clarke AR, Tosh D. Liver zonation occurs through a beta-catenin-dependent, c-Myc-independent mechanism. Gastroenterology. 2009;136(7):2316–2324–3.Google Scholar
  75. 75.
    Sato A, Kadokura K, Uchida H, Tsukada K. An in vitro hepatic zonation model with a continuous oxygen gradient in a microdevice. Biochem Biophys Res Commun. 2014;453(4):767–71.PubMedGoogle Scholar
  76. 76.
    Allen JW, Khetani SR, Bhatia SN. In vitro zonation and toxicity in a hepatocyte bioreactor. Toxicol Sci. 2005;84(1):110–9.PubMedGoogle Scholar
  77. 77.
    Larrosa-Haro A, Sáenz-Rivera C, González-Ortiz M, Coello-Ramírez P, Vázquez-Camacho G. Lack of cholesterol-lowering effect of graded doses of cholestyramine in children with Alagille syndrome: a pilot study. J Pediatr Gastroenterol Nutr. 2003;36(1):50–3.PubMedGoogle Scholar
  78. 78.
    Najimi M, Defresne F, Sokal EM. Concise review: updated advances and current challenges in cell therapy for inborn liver metabolic defects. Stem Cells Transl Med. 2016;5(8):1117–25.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Zhao D, Chen S, Cai J, Guo Y, Song Z, Che J, et al. Derivation and characterization of hepatic progenitor cells from human embryonic stem cells. Verfaillie CM, editor. PLoS One. 2009;4(7):e6468.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Sampaziotis F, Cardoso de Brito M, Madrigal P, Bertero A, Saeb-Parsy K, FAC S, et al. Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation. Nat Biotechnol. 2015;33(8):845–52.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Dianat N, Dubois-Pot-Schneider H, Steichen C, Desterke C, Leclerc P, Raveux A, et al. Generation of functional cholangiocyte-like cells from human pluripotent stem cells and HepaRG cells. Hepatology. 2014;60(2):700–14.PubMedPubMedCentralGoogle Scholar
  82. 82.
    De Assuncao TM, Sun Y, Jalan-Sakrikar N, Drinane MC, Huang BQ, Li Y, et al. Development and characterization of human-induced pluripotent stem cell-derived cholangiocytes. Lab Investig. 2015;95(6):684–96.PubMedGoogle Scholar
  83. 83.
    Ogawa M, Ogawa S, Bear CE, Ahmadi S, Chin S, Li B, et al. Directed differentiation of cholangiocytes from human pluripotent stem cells. Nat Biotechnol. 2015;33(8):853–61.PubMedGoogle Scholar
  84. 84.
    Ghanekar A, Kamath BM. Cholangiocytes derived from induced pluripotent stem cells for disease modeling. Curr Opin Gastroenterol. 2016;32(3):210–5.PubMedGoogle Scholar
  85. 85.
    Fujino H, Hiramatsu H, Tsuchiya A, Niwa A, Noma H, Shiota M, et al. Human cord blood CD34+ cells develop into hepatocytes in the livers of NOD/SCID/ cnull mice through cell fusion. FASEB J. 2007;21(13):3499–510.PubMedGoogle Scholar
  86. 86.
    Skvorak KJ, Dorko K, Marongiu F, Tahan V, Hansel MC, Gramignoli R, et al. Placental stem cell correction of murine intermediate maple syrup urine disease. Hepatology. 2013;57(3):1017–23.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Skvorak KJ, Dorko K, Marongiu F, Tahan V, Hansel MC, Gramignoli R, et al. Improved amino acid, bioenergetic metabolite and neurotransmitter profiles following human amnion epithelial cell transplant in intermediate maple syrup urine disease mice. Mol Genet Metab. 2013;109(2):132–8.PubMedGoogle Scholar
  88. 88.
    Manuelpillai U, Tchongue J, Lourensz D, Vaghjiani V, Samuel CS, Liu A, et al. Transplantation of human amnion epithelial cells reduces hepatic fibrosis in immunocompetent CCl 4 -treated mice. Cell Transplant. 2010;19(9):1157–68.PubMedGoogle Scholar
  89. 89.
    Kehat I, Kenyagin-Karsenti D, Snir M, Segev H, Amit M, Gepstein A, et al. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest. 2001;108(3):407–14.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Yang L, Soonpaa MH, Adler ED, Roepke TK, Kattman SJ, Kennedy M, et al. Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population. Nature. 2008;453(7194):524–8.PubMedGoogle Scholar
  91. 91.
    Burridge PW, Matsa E, Shukla P, Lin ZC, Churko JM, Ebert AD, et al. Chemically defined generation of human cardiomyocytes. Nat Methods. 2014;11(8):855–60.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Bellamy V, Vanneaux V, Bel A, Nemetalla H, Emmanuelle Boitard S, Farouz Y, et al. Long-term functional benefits of human embryonic stem cell-derived cardiac progenitors embedded into a fibrin scaffold. J Heart Lung Transplant. 2015;34(9):1198–207.PubMedGoogle Scholar
  93. 93.
    Blin G, Nury D, Stefanovic S, Neri T, Guillevic O, Brinon B, et al. A purified population of multipotent cardiovascular progenitors derived from primate pluripotent stem cells engrafts in postmyocardial infarcted nonhuman primates. J Clin Invest. 2010;120(4):1125–39.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Laflamme MA, Chen KY, Naumova AV, Muskheli V, Fugate JA, Dupras SK, et al. Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol. 2007;25(9):1015–24.PubMedGoogle Scholar
  95. 95.
    Tajiri N, Acosta S, Portillo-Gonzales GS, Aguirre D, Reyes S, Lozano D, et al. Therapeutic outcomes of transplantation of amniotic fluid-derived stem cells in experimental ischemic stroke. Front Cell Neurosci. 2014;8:227.PubMedPubMedCentralGoogle Scholar
  96. 96.
    Bartolucci JG, Verdugo FJ, González PL, Larrea RE, Abarzua E, Goset C, et al. Safety and Efficacy of the Intravenous Infusion of Umbilical Cord Mesenchymal Stem Cells in Patients With Heart Failure: A Phase 1/2 Randomized Controlled Trial (RIMECARD Trial). Circ Res. 2017;121(10):1192–204.PubMedGoogle Scholar
  97. 97.
    Spinner NB, Leonard LD, Krantz ID. Alagille syndrome. GeneReviews(®). Seattle: University of Washington; 2013.Google Scholar
  98. 98.
    Ziesenitz V, Köhler D, Gläser C, Loukanov T, Gorenflo M. PO-0050 absent pulmonary valve in a patient with Alagille syndrome. Arch Dis Child. 2014;99(Suppl 2):A266.2–A266.Google Scholar
  99. 99.
    Funk M, Cohen M, Santana O. Alagille syndrome: an unusual presentation of an uncommon disease. South Med J. 2010;103(10):1049–51.PubMedGoogle Scholar
  100. 100.
    Della Rocca F, Sartore S, Guidolin D, Bertiplaglia B, Gerosa G, Casarotto D, et al. Cell composition of the human pulmonary valve: a comparative study with the aortic valve--the VESALIO Project. Vitalitate Exornatum succedaneum Aorticum labore Ingegnoso Obtinebitur. Ann Thorac Surg. 2000;70(5):1594–600.PubMedGoogle Scholar
  101. 101.
    VeDepo MC, Detamore MS, Hopkins RA, Converse GL. Recellularization of decellularized heart valves: progress toward the tissue-engineered heart valve. J Tissue Eng. 2017;8:2041731417726327.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Ott HC, Matthiesen TS, Goh S-K, Black LD, Kren SM, Netoff TI, et al. Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat Med. 2008;14(2):213–21.PubMedGoogle Scholar
  103. 103.
    Uygun BE, Soto-Gutierrez A, Yagi H, Izamis M-L, Guzzardi MA, Shulman C, et al. Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat Med. 2010;16(7):814–20.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Ko IK, Peng L, Peloso A, Smith CJ, Dhal A, Deegan DB, et al. Bioengineered transplantable porcine livers with re-endothelialized vasculature. Biomaterials. 2015;40:72–9.PubMedGoogle Scholar
  105. 105.
    Uygun BE, Izamis M-L, Jaramillo M, Chen Y, Price G, Ozer S, et al. Discarded livers find a new life: engineered liver grafts using hepatocytes recovered from marginal livers. Artif Organs. 2017;41(6):579–85.PubMedGoogle Scholar
  106. 106.
  107. 107.
    Andersson ER, Lendahl U. Therapeutic modulation of Notch signalling--are we there yet? Nat Rev Drug Discov. 2014;13(5):357–78.PubMedGoogle Scholar
  108. 108.
    Keeling KM, Xue X, Gunn G, Bedwell DM. Therapeutics based on stop codon readthrough. Annu Rev Genomics Hum Genet. 2014;15(1):371–94.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Zucchelli S, Patrucco L, Persichetti F, Gustincich S, Cotella D. Engineering translation in mammalian cell factories to increase protein yield: the unexpected use of long non-coding SINEUP RNAs. Comput Struct Biotechnol J. 2016;14:404–10.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Jiang F, Doudna JA. CRISPR–Cas9 structures and mechanisms. Annu Rev Biophys. 2017;46(1):505–29.PubMedGoogle Scholar
  111. 111.
    Riely CA, Cotlier E, Jensen PS, Klatskin G. Arteriohepatic dysplasia: a benign syndrome of intrahepatic cholestasis with multiple organ involvement. Ann Intern Med. 1979;91(4):520–7.PubMedGoogle Scholar
  112. 112.
    Roskams T, Desmet V. Embryology of extra- and intrahepatic bile ducts, the ductal plate. Anat Rec Adv Integr Anat Evol Biol. 2008;291(6):628–35.Google Scholar
  113. 113.
    Andersson ER, Lendahl U. Therapeutic modulation of Notch signalling — are we there yet? Nat Rev Drug Discov. 2014;13(5):357–78.PubMedGoogle Scholar
  114. 114.
    Ye Q, Jiang J, Zhan G, Yan W, Huang L, Hu Y, et al. Small molecule activation of NOTCH signaling inhibits acute myeloid leukemia. Sci Rep. 2016;6(1):26510.PubMedPubMedCentralGoogle Scholar
  115. 115.
    Weijzen S, Velders MP, Elmishad AG, Bacon PE, Panella JR, Nickoloff BJ, et al. The Notch ligand Jagged-1 is able to induce maturation of monocyte-derived human dendritic cells. J Immunol. 2002;169(8):4273–8.PubMedGoogle Scholar
  116. 116.
    Nickoloff B, Qin J, Chaturvedi V, Denning M, Bonish B, Miele L. Jagged-1 mediated activation of Notch signaling induces complete maturation of human keratinocytes through NF-kB and PPARg. Cell Death Differ. 2002;9:842–55.PubMedGoogle Scholar
  117. 117.
    Zhao X-C, Dou G-R, Wang L, Liang L, Tian D-M, Cao X-L, et al. Inhibition of tumor angiogenesis and tumor growth by the DSL domain of Human Delta-like 1 targeted to vascular endothelial cells. Neoplasia. 2013;15(7):815–IN32.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Nichols JT, Miyamoto A, Olsen SL, D’Souza B, Yao C, Weinmaster G. DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur. J Cell Biol. 2007;176(4):445–58.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Youngstrom DW, Senos R, Zondervan RL, Brodeur JD, Lints AR, Young DR, et al. Intraoperative delivery of the Notch ligand Jagged-1 regenerates appendicular and craniofacial bone defects. NPJ Regen Med. 2017;2:32.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Olsen IE, Ittenbach RF, Rovner AJ, Leonard MB, Mulberg AE, Stallings VA, et al. Deficits in size-adjusted bone mass in children with Alagille syndrome. J Pediatr Gastroenterol Nutr. 2005;40(1):76–82.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics--developing a new class of drugs. Nat Rev Drug Discov. 2014;13(10):759–80.PubMedGoogle Scholar
  122. 122.
    Grochowski CM, Loomes KM, Spinner NB. Jagged1 (JAG1): structure, expression, and disease associations. Gene. 2016;576(1 Pt 3):381–4.PubMedGoogle Scholar
  123. 123.
    Mašek J, Andersson ERER. The developmental biology of genetic Notch disorders. Development. 2017;144(10):1743–63.PubMedGoogle Scholar
  124. 124.
    McDaniell R, Warthen DM, Sanchez-Lara PA, Pai A, Krantz ID, Piccoli DA, et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the NOTCH signaling pathway. Am J Hum Genet. 2006;79(1):169–73.PubMedPubMedCentralGoogle Scholar
  125. 125.
    Kamath BM, Bauer RC, Loomes KM, Chao G, Gerfen J, Hutchinson A, et al. NOTCH2 mutations in Alagille syndrome. J Med Genet. 2012;49(2):138–44.Google Scholar
  126. 126.
    Stenson PD, Mort M, Ball EV, Shaw K, Phillips AD, Cooper DN. The human gene mutation database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet. 2014;133(1):1–9.PubMedGoogle Scholar
  127. 127.
    McCaughan KK, Brown CM, Dalphin ME, Berry MJ, Tate WP. Translational termination efficiency in mammals is influenced by the base following the stop codon. Proc Natl Acad Sci. 1995;92(12):5431–5.PubMedGoogle Scholar
  128. 128.
    Tate WP, Poole ES, Horsfield JA, Mannering SA, Brown CM, Moffat JG, et al. Translational termination efficiency in both bacteria and mammals is regulated by the base following the stop codon. Biochem Cell Biol. 1995;73(11–12):1095–103.PubMedGoogle Scholar
  129. 129.
    Manuvakhova M, Keeling K, Bedwell DM. Aminoglycoside antibiotics mediate context-dependent suppression of termination codons in a mammalian translation system. RNA. 2000;6(7):1044–55.PubMedPubMedCentralGoogle Scholar
  130. 130.
    Cassan M, Rousset JP. UAG readthrough in mammalian cells: effect of upstream and downstream stop codon contexts reveal different signals. BMC Mol Biol. 2001;2:3.PubMedPubMedCentralGoogle Scholar
  131. 131.
    Howard M, Frizzell RA, Bedwell DM. Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations. Nat Med. 1996;2(4):467–9.PubMedGoogle Scholar
  132. 132.
    Recht MI, Douthwaite S, Puglisi JD, Davies J, Noller HF. Basis for prokaryotic specificity of action of aminoglycoside antibiotics. EMBO J. 1999;18(11):3133–8.PubMedPubMedCentralGoogle Scholar
  133. 133.
    Du M, Jones JR, Lanier J, Keeling KM, Lindsey JR, Tousson A, et al. Aminoglycoside suppression of a premature stop mutation in a Cftr-/- mouse carrying a human CFTR-G542X transgene. J Mol Med. 2002;80(9):595–604.PubMedGoogle Scholar
  134. 134.
    Sangkuhl K, Schulz A, Römpler H, Yun J, Wess J, Schöneberg T. Aminoglycoside-mediated rescue of a disease-causing nonsense mutation in the V2 vasopressin receptor gene in vitro and in vivo. Hum Mol Genet. 2004;13(9):893–903.PubMedGoogle Scholar
  135. 135.
    Clancy JP, Bebök Z, Ruiz F, King C, Jones J, Walker L, et al. Evidence that systemic gentamicin suppresses premature stop mutations in patients with cystic fibrosis. Am J Respir Crit Care Med. 2001;163(7):1683–92.PubMedGoogle Scholar
  136. 136.
    Wilschanski M, Yahav Y, Yaacov Y, Blau H, Bentur L, Rivlin J, et al. Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations. N Engl J Med. 2003;349(15):1433–41.PubMedGoogle Scholar
  137. 137.
    Malik V, Rodino-Klapac LR, Viollet L, Wall C, King W, Al-Dahhak R, et al. Gentamicin-induced readthrough of stop codons in Duchenne muscular dystrophy. Ann Neurol. 2010;67(6):771–80.PubMedGoogle Scholar
  138. 138.
    Politano L, Nigro G, Nigro V, Piluso G, Papparella S, Paciello O, et al. Gentamicin administration in Duchenne patients with premature stop codon. Preliminary results. Acta Myol. 2003;22(1):15–21.PubMedGoogle Scholar
  139. 139.
    Baradaran-Heravi A, Niesser J, Balgi AD, Choi K, Zimmerman C, South AP, et al. Gentamicin B1 is a minor gentamicin component with major nonsense mutation suppression activity. Proc Natl Acad Sci U S A. 2017;114(13):3479–84.PubMedPubMedCentralGoogle Scholar
  140. 140.
    Aburano T, Yokoyama K, Takayama T, Tonami N, Hisada K. Distinct hepatic retention of Tc-99m IDA in arteriohepatic dysplasia (Alagille syndrome). Clin Nucl Med. 1989;14(12):874–6.PubMedGoogle Scholar
  141. 141.
    Libbrecht L, Spinner NB, Moore EC, Cassiman D, Van Damme-Lombaerts R, Roskams T. Peripheral bile duct paucity and cholestasis in the liver of a patient with Alagille syndrome: further evidence supporting a lack of postnatal bile duct branching and elongation. Am J Surg Pathol. 2005;29(6):820–6.Google Scholar
  142. 142.
    Carrieri C, Cimatti L, Biagioli M, Beugnet A, Zucchelli S, Fedele S, et al. Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat. Nature. 2012;491(7424):454–7.PubMedGoogle Scholar
  143. 143.
    Zucchelli S, Fasolo F, Russo R, Cimatti L, Patrucco L, Takahashi H, et al. SINEUPs are modular antisense long non-coding RNAs that increase synthesis of target proteins in cells. Front Cell Neurosci. 2015;9:174.PubMedPubMedCentralGoogle Scholar
  144. 144.
    Zucchelli S, Cotella D, Takahashi H, Carrieri C, Cimatti L, Fasolo F, et al. SINEUPs: a new class of natural and synthetic antisense long non-coding RNAs that activate translation. RNA Biol. 2015;12(8):771–9.PubMedPubMedCentralGoogle Scholar
  145. 145.
    Thakurdas SM, Lopez MF, Kakuda S, Fernandez-Valdivia R, Zarrin-Khameh N, Haltiwanger RS, et al. Jagged1 heterozygosity in mice results in a congenital cholangiopathy which is reversed by concomitant deletion of one copy of Poglut1 (Rumi). Hepatology. 2016;63(2):550–65.Google Scholar
  146. 146.
    Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337(6096):816–21.PubMedGoogle Scholar
  147. 147.
    Cong L, Ann Ran F, Cox D, Lin S, Barretto R, Habib N, et al. Multiplex Genome Engineering Using CRIPSR/Cas Systems. Science. 2013;339:819–23.PubMedPubMedCentralGoogle Scholar
  148. 148.
    Long C, McAnally JR, Shelton JM, Mireault AA, Bassel-Duby R, Olson EN. Prevention of muscular dystrophy in mice by CRISPR/Cas9-mediated editing of germline DNA. Science. 2014;345(6201):1184–8.PubMedPubMedCentralGoogle Scholar
  149. 149.
    Lieber MR. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem. 2010;79:181–211.PubMedPubMedCentralGoogle Scholar
  150. 150.
    San Filippo J, Sung P, Klein H. Mechanism of eukaryotic homologous recombination. Annu Rev Biochem. 2008;77(1):229–57.PubMedGoogle Scholar
  151. 151.
    Long C, Amoasii L, Mireault AA, McAnally JR, Li H, Sanchez-Ortiz E, et al. Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science. 2016;351(6271):400–3.PubMedGoogle Scholar
  152. 152.
    Nelson CE, Hakim CH, Ousterout DG, Thakore PI, Moreb EA, Castellanos Rivera RM, et al. In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science. 2016;351(6271):403–7.PubMedGoogle Scholar
  153. 153.
    Tabebordbar M, Zhu K, Cheng JKW, Chew WL, Widrick JJ, Yan WX, et al. In vivo gene editing in dystrophic mouse muscle and muscle stem cells. Science. 2016;351(6271):407–11.PubMedGoogle Scholar
  154. 154.
    Yang Y, Wang L, Bell P, McMenamin D, He Z, White J, et al. A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice. Nat Biotechnol. 2016;34(3):334–8.PubMedPubMedCentralGoogle Scholar
  155. 155.
    Walter TJ, Vanderpool C, Cast AE, Huppert SS. Intrahepatic bile duct regeneration in mice does not require Hnf6 or Notch signaling through Rbpj. Am J Pathol. 2014;184(5):1479–88.PubMedPubMedCentralGoogle Scholar
  156. 156.
    Yanger K, Zong Y, Maggs LR, Shapira SN, Maddipati R, Aiello NM, et al. Robust cellular reprogramming occurs spontaneously during liver regeneration. Genes Dev. 2013;27(7):719–24.PubMedPubMedCentralGoogle Scholar
  157. 157.
    Yu B, He Z-Y, You P, Han Q-W, Xiang D, Chen F, et al. Reprogramming fibroblasts into bipotential hepatic stem cells by defined factors. Cell Stem Cell. 2013;13(3):328–40.PubMedGoogle Scholar
  158. 158.
    Chen R, Desai NR, Ross JS, Zhang W, Chau KH, Wayda B, et al. Publication and reporting of clinical trial results: cross sectional analysis across academic medical centers. BMJ. 2016;352:i637.PubMedPubMedCentralGoogle Scholar
  159. 159.
    Kicinski M. How does under-reporting of negative and inconclusive results affect the false-positive rate in meta-analysis? A simulation study. BMJ Open. 2014;4(8):e004831.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Karolinska InstitutetSolnaSweden

Personalised recommendations