title: Liver bioengineering: from the stage of liver decellularized matrix to the multiple cellular actors and bioreactor special effects.
abstract: Liver bioengineering has been a field of intense research and popular excitement in the past decades. It experiences great interest since the introduction of whole liver acellular scaffolds generated by perfusion decellularization (1-3). Nevertheless, the different strategies developed so far have failed to generate hepatic tissue in vitro bioequivalent to native liver tissue. Even notable novel strategies that rely on iPSC-derived liver progenitor cells potential to self-organize in association with endothelial cells in hepatic organoids are lacking critical components of the native tissue (e.g., bile ducts, functional vascular network, hepatic microarchitecture, etc) (4). Hence, it is vital to understand the strengths and short comes of our current strategies in this quest to re-create liver organogenesis in vitro. To shed some light into these issues, this review describes the different actors that play crucial roles in liver organogenesis and highlights the steps still missing to successfully generate whole livers and hepatic organoids in vitro for multiple applications.
authors.affiliation: Vall d'Hebron University Hospital; Universitat Autònoma de Barcelona; Barcelona, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Caralt
authors.affiliation: Gregorio Marañón University Hospital; Madrid, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Velasco
authors.affiliation: University of Zaragoza; Zaragoza, Spain; IIS Aragón; CIBERehd; Zaragoza, Spain; Aragon Health Sciences Institute (IACS); Zaragoza, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Lanas
authors.affiliation: University of Zaragoza; Zaragoza, Spain; IIS Aragón; CIBERehd; Zaragoza, Spain; Aragon Health Sciences Institute (IACS); Zaragoza, Spain.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Baptista
mesh_terms: D000818:Animals; D057005:Bioengineering / Q000379:methods*; D019149:Bioreactors; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000502:physiology*; D055153:Stem Cell Niche; D054457:Tissue Scaffolds
keywords: bile duct morphogenesis; hepatoblasts; liver bioengineering; liver decellularization; liver organogenesis; liver stem cell differentiation; organ bioengineering
references.citation: Nat Med. 2012 Mar 04;18(4):572-9
references.pmid: 22388089
references.citation: Nat Med. 2008 Feb;14(2):213-21
references.pmid: 18193059
references.citation: Biotechnol Bioeng. 2000 Aug 20;69(4):359-69
references.pmid: 10862674
references.citation: Cell Res. 2009 Nov;19(11):1233-42
references.pmid: 19736565
references.citation: Curr Opin Biotechnol. 2014 Feb;25:45-50
references.pmid: 24484880
references.citation: Cell Transplant. 2003;12(1):1-11
references.pmid: 12693659
references.citation: J Cell Biol. 2010 Jun 28;189(7):1075-7
references.pmid: 20584914
references.citation: J Cell Sci. 2011 Jan 1;124(Pt 1):9-18
references.pmid: 21172819
references.citation: Ann Biomed Eng. 2006 Nov;34(11):1729-44
references.pmid: 17031599
references.citation: Hepatology. 2010 May;51(5):1810-9
references.pmid: 20432258
references.citation: J Cell Sci. 2010 Jan 1;123(Pt 1):29-39
references.pmid: 20016064
references.citation: Transpl Immunol. 2002 Jun;10(1):15-24
references.pmid: 12182460
references.citation: Science. 2005 Nov 18;310(5751):1139-43
references.pmid: 16293750
references.citation: J Cell Biochem. 2011 Jan;112(1):1-9
references.pmid: 20626029
references.citation: Tissue Eng Part C Methods. 2009 Mar;15(1):41-55
references.pmid: 19267518
references.citation: Biomaterials. 2010 May;31(14):3793-803
references.pmid: 20171732
references.citation: Hepatology. 1998 Sep;28(3):843-50
references.pmid: 9731582
references.citation: Annu Int Conf IEEE Eng Med Biol Soc. 2009;2009:6526-9
references.pmid: 19964173
references.citation: J Clin Gastroenterol. 2005 Apr;39(4 Suppl 2):S158-61
references.pmid: 15758652
references.citation: Nature. 2013 Jul 25;499(7459):481-4
references.pmid: 23823721
references.citation: Science. 2010 Jul 30;329(5991):538-41
references.pmid: 20576850
references.citation: Int Rev Cytol. 2007;259:1-48
references.pmid: 17425938
references.citation: Science. 2003 Feb 7;299(5608):890-3
references.pmid: 12574630
references.citation: J Cell Biol. 1995 Nov;131(3):791-805
references.pmid: 7593197
references.citation: J Hepatol. 1998 Nov;29(5):752-9
references.pmid: 9833913
references.citation: Nat Biotechnol. 2006 Nov;24(11):1412-9
references.pmid: 17086173
references.citation: Development. 2009 May;136(10):1727-39
references.pmid: 19369401
references.citation: Nat Med. 2010 Jul;16(7):814-20
references.pmid: 20543851
references.citation: Nat Med. 2010 Aug;16(8):927-33
references.pmid: 20628374
references.citation: J Biochem. 2011 Mar;149(3):231-9
references.pmid: 21217146
references.citation: Virchows Arch A Pathol Anat Histopathol. 1993;423(2):77-84
references.pmid: 8212543
references.citation: Stem Cell Rev. 2005;1(3):253-60
references.pmid: 17142862
references.citation: Tissue Eng. 2003 Aug;9(4):757-66
references.pmid: 13678452
references.citation: J Vasc Surg. 1997 Apr;25(4):757-63
references.pmid: 9129636
references.citation: Curr Top Dev Biol. 2006;72:205-36
references.pmid: 16564336
references.citation: Biochem J. 1999 May 1;339 ( Pt 3):481-8
references.pmid: 10215583
references.citation: Nat Biotechnol. 2008 Jan;26(1):120-6
references.pmid: 18026090
references.citation: Nat Rev Mol Cell Biol. 2010 Apr;11(4):288-300
references.pmid: 20308986
references.citation: Biomaterials. 2011 Oct;32(30):7389-402
references.pmid: 21788068
references.citation: Am J Physiol Gastrointest Liver Physiol. 2007 Dec;293(6):G1147-54
references.pmid: 17932231
references.citation: Mol Biol Cell. 2006 Jan;17(1):345-56
references.pmid: 16251347
references.citation: Tissue Eng Part C Methods. 2011 Jun;17(6):677-86
references.pmid: 21375407
references.citation: Organogenesis. 2010 Apr-Jun;6(2):134-6
references.pmid: 20885860
references.citation: EMBO J. 1999 Apr 15;18(8):2127-36
references.pmid: 10205167
references.citation: Gastroenterology. 1991 Jul;101(1):200-6
references.pmid: 2044908
references.citation: Semin Immunol. 2008 Apr;20(2):109-16
references.pmid: 18083531
references.citation: Virchows Arch A Pathol Anat Histopathol. 1993;423(1):1-11
references.pmid: 8212529
references.citation: Dev Cell. 2010 Feb 16;18(2):175-89
references.pmid: 20159590
references.citation: Cell. 2006 Aug 25;126(4):677-89
references.pmid: 16923388
references.citation: Biochim Biophys Acta. 2002 Nov 11;1592(3):303-12
references.pmid: 12421674
references.citation: Am J Physiol Cell Physiol. 2013 Jun 1;304(11):C1053-63
references.pmid: 23485712
references.citation: Cell. 2002 Sep 20;110(6):673-87
references.pmid: 12297042
references.citation: Hepatology. 2010 Oct;52(4):1443-54
references.pmid: 20721882
references.citation: J Surg Res. 2012 Mar;173(1):e11-25
references.pmid: 22099595
references.citation: Mech Dev. 2003 Jan;120(1):81-7
references.pmid: 12490298
references.citation: Annu Rev Biomed Eng. 2011 Aug 15;13:27-53
references.pmid: 21417722
references.citation: Cell Adh Migr. 2010 Apr-Jun;4(2):194-8
references.pmid: 20179422
references.citation: J Cell Sci. 2004 Jul 1;117(Pt 15):3165-74
references.pmid: 15226394
references.citation: Hepatology. 2011 Mar;53(3):1035-45
references.pmid: 21374667
references.citation: J Biol Chem. 2005 Feb 11;280(6):4544-52
references.pmid: 15590642
references.citation: Am J Pathol. 1993 May;142(5):1483-92
references.pmid: 7684197
references.citation: Gastroenterology. 2009 Jul;137(1):62-79
references.pmid: 19328801
references.citation: Tissue Eng Part A. 2010 Jun;16(6):2007-16
references.pmid: 20088704
references.citation: Tissue Eng Part C Methods. 2011 May;17(5):557-68
references.pmid: 21210720
references.citation: Hepatology. 2008 Apr;47(4):1394-400
references.pmid: 18307210
references.citation: Hepatology. 2011 Feb;53(2):604-17
references.pmid: 21274881
references.citation: Hepatology. 1992 Jun;15(6):1198-203
references.pmid: 1592356
references.citation: Ann Surg. 2010 Aug;252(2):351-7
references.pmid: 20647924
references.citation: Exp Clin Transplant. 2012 Apr;10(2):87-100
references.pmid: 22432750
references.citation: Clin Liver Dis. 2006 Feb;10(1):1-25, v
references.pmid: 16376792
references.citation: FASEB J. 1995 Nov;9(14):1401-10
references.pmid: 7589981
references.citation: Hepatology. 1998 Mar;27(3):839-47
references.pmid: 9500715
references.citation: Tissue Eng Part A. 2008 Jan;14(1):59-70
references.pmid: 18333805
references.citation: Gastroenterology. 2009 Jun;136(7):2325-33
references.pmid: 19403103
references.citation: Hepatology. 2007 Oct;46(4):1246-56
references.pmid: 17625791
references.citation: Cell Transplant. 2013;22(2):231-42
references.pmid: 22943797
references.citation: Biochim Biophys Acta. 2008 Feb;1782(2):61-74
references.pmid: 18187050
references.citation: Ann N Y Acad Sci. 2001 Nov;944:398-419
references.pmid: 11797689