title: Hepatic differentiation of human amniotic epithelial cells and in vivo therapeutic effect on animal model of cirrhosis.
abstract: OBJECTIVE
  Human amniotic epithelial cells (hAECs) have been touted as an ideal stem cell candidate, being ethically neutral, immunologically naïve, plentiful in origin, and retaining plasticity in its fetal stage. We hypothesized that by applying natural physiological signals of the developing liver, hAECs can be coaxed into becoming functional immunopermissive hepatocyte-like cells. These cells would have tremendous potential for allogenic cellular transplantation in the treatment of chronic liver insufficiency.
  
  
  METHODS
  hAECs were obtained from term placentas and subjected to hepatic trans-differentiation. Hepatic differentiated cells were analyzed with immunophenotyping, electron microscopy, reverse transcription-polymerase chain reaction as well as characterized for hepatic metabolic function. In vivo efficacy was tested using intrasplenic transplantation into non-obese diabetic (NOD) Scid Gamma mice with thioacetamide-induced chronic liver failure and analyzed for engraftment and improvement in liver indices.
  
  
  RESULTS
  With hepatic differentiation, hAECs assumed a hepatocytic polygonal morphology with upregulation of transcription factors responsible for liver specification. These hepatic differentiated-hAECs (HD-AECs) demonstrated bile canaliculi formation, secreted albumin, eliminated indo-cyanine green, uptook low-density lipoprotein, and inducible CYP3A4 and CYP2C9 enzymatic activities. Transplantation of HD-AECs and de novo hAECs in mice model of cirrhosis showed successful in vivo engraftment and differentiation into functional hepatocytes positive for human-specific albumin. HD-AEC cells that had undergone hepatic differentiation showed the greatest improvement in albumin function while preserving human leukocyte antigen-G expression postdifferentiation.
  
  
  CONCLUSIONS
  hAECs were able to differentiate into functional hepatocyte-like cells both in vivo and in vitro. They showed therapeutic efficacy after transplantation in mice model of cirrhosis, offering an exciting source of cells for generation of functionally useful hepatocytes.
authors.affiliation: Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Jaymie Siqi
authors.initials: JS
authors.lastname: Lin
authors.affiliation: Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Antony
authors.initials: A
authors.lastname: Sagayaraj
authors.affiliation: Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Nur Halisah Bte
authors.initials: NH
authors.lastname: Jumat
authors.affiliation: Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Choolani
authors.affiliation: Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore.|Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Jerry Kok Yen
authors.initials: JK
authors.lastname: Chan
authors.affiliation: Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Arijit
authors.initials: A
authors.lastname: Biswas
authors.affiliation: Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Peng Cheang
authors.initials: PC
authors.lastname: Wong
authors.affiliation: Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Seng Gee
authors.initials: SG
authors.lastname: Lim
authors.affiliation: Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Division of Gastroenterology and Hepatology, University Medicine Cluster, National University Health System, Singapore.
authors.forename: Yock Young
authors.initials: YY
authors.lastname: Dan
mesh_terms: D000418:Albumins; D000650:Amnion / Q000166:cytology*; D000818:Animals; D002454:Cell Differentiation; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology* / Q000637:transplantation; D005260:Female; D022781:Hepatocytes / Q000166:cytology* / Q000637:transplantation; D006801:Humans; D008103:Liver Cirrhosis / Q000628:therapy*; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD
chemical_list: D000418:Albumins
keywords: amniotic membrane; chronic liver failure; fibrosis; hepatic differentiation; liver