title: Inhibition of activin/nodal signalling is necessary for pancreatic differentiation of human pluripotent stem cells.
abstract: OBJECTIVE
  Human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hIPSCs) offer unique opportunities for regenerative medicine and for the study of mammalian development. However, developing methods to differentiate hESCs/hIPSCs into specific cell types following a natural pathway of development remains a major challenge.
  
  
  METHODS
  We used defined culture media to identify signalling pathways controlling the differentiation of hESCs/hIPSCs into pancreatic or hepatic progenitors. This approach avoids the use of feeders, stroma cells or serum, all of which can interfere with experimental outcomes and could preclude future clinical applications.
  
  
  RESULTS
  This study reveals, for the first time, that activin/TGF-β signalling blocks pancreatic specification induced by retinoic acid while promoting hepatic specification in combination with bone morphogenetic protein and fibroblast growth factor. Using this knowledge, we developed culture systems to differentiate human pluripotent stem cells into near homogenous population of pancreatic and hepatic progenitors displaying functional characteristics specific to their natural counterparts. Finally, functional experiments showed that activin/TGF-β signalling achieves this essential function by controlling the levels of transcription factors necessary for liver and pancreatic development, such as HEX and HLXB9.
  
  
  CONCLUSIONS
  Our methods of differentiation provide an advantageous system to model early human endoderm development in vitro, and also represent an important step towards the generation of pancreatic and hepatic cells for clinical applications.
authors.affiliation: Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, West Forvie Site, Robinson Way, Cambridge, UK.
authors.forename: C H-H
authors.initials: CH
authors.lastname: Cho
authors.forename: N R-F
authors.initials: NR
authors.lastname: Hannan
authors.forename: F M
authors.initials: FM
authors.lastname: Docherty
authors.forename: H M
authors.initials: HM
authors.lastname: Docherty
authors.forename: M
authors.initials: M
authors.lastname: Joåo Lima
authors.forename: M W B
authors.initials: MW
authors.lastname: Trotter
authors.forename: K
authors.initials: K
authors.lastname: Docherty
authors.forename: L
authors.initials: L
authors.lastname: Vallier
mesh_terms: D028341:Activins / Q000037:antagonists & inhibitors*; D000818:Animals; D002450:Cell Communication; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D044968:Regenerative Medicine; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D016212:Transforming Growth Factor beta; D028341:Activins; D014212:Tretinoin