BMP-4 is required for hepatic specification of mouse embryonic stem cell-derived definitive endoderm.
When differentiated in the presence of activin A in serum-free conditions, mouse embryonic stem cells efficiently generate an endoderm progenitor population defined by the coexpression of either Brachyury, Foxa2 and c-Kit, or c-Kit and Cxcr4. Specification of these progenitors with bone morphogenetic protein-4 in combination with basic fibroblast growth factor and activin A results in the development of hepatic populations highly enriched (45-70%) for cells that express the alpha-fetoprotein and albumin proteins. These cells also express transcripts of Afp, Alb1, Tat, Cps1, Cyp7a1 and Cyp3a11; they secrete albumin, store glycogen, show ultrastructural characteristics of mature hepatocytes, and are able to integrate into and proliferate in injured livers in vivo and mature into hepatocytes expressing dipeptidyl peptidase IV or fumarylacetoacetate hydrolase. Together, these findings establish a developmental pathway in embryonic stem cell differentiation cultures that leads to efficient generation of cells with an immature hepatocytic phenotype.
Gouon-Evans
Valerie
V
Department of Gene and Cell Medicine, Black Family Stem Cell Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA.
Boussemart
Lise
L
Gadue
Paul
P
Nierhoff
Dirk
D
Koehler
Christoph I
CI
Kubo
Atsushi
A
Shafritz
David A
DA
Keller
Gordon
G
D028341:Activins / Q000502:physiology; D000418:Albumins / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D015704:CD4 Antigens / Q000235:genetics; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D017690:Cell Transplantation / Q000379:methods / Q000502:physiology*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000502:physiology*; D004707:Endoderm / Q000166:cytology / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000032:analysis; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology*; D006867:Hydrolases / Q000378:metabolism; D051379:Mice; D010641:Phenotype; D015398:Signal Transduction
D000418:Albumins; D015415:Biomarkers; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D015704:CD4 Antigens; C496503:Foxa2 protein, mouse; C422405:activin A; D028341:Activins; D051542:Hepatocyte Nuclear Factor 3-beta; D049452:Green Fluorescent Proteins; D006003:Glycogen; D006867:Hydrolases; D018819:Dipeptidyl Peptidase 4; C020156:fumarylacetoacetase