Activin and BMP4 Synergistically Promote Formation of Definitive Endoderm in Human Embryonic Stem Cells

Human embryonic stem cells (hESCs) herald tremendous promise for the production of clinically useful cell types for the treatment of injury and disease. Numerous reports demonstrate their differentiation into definitive endoderm (DE) cells, the germ layer from which pancreatic β cells and hepatocyte...

Full description

Saved in:
Bibliographic Details
Published inStem cells (Dayton, Ohio) Vol. 30; no. 4; pp. 631 - 642
Main Authors Teo, Adrian K. K., Ali, Yusuf, Wong, Kee Yew, Chipperfield, Hiram, Sadasivam, Akila, Poobalan, Yogavalli, Tan, Ee Kim, Wang, Siew Tein, Abraham, Suman, Tsuneyoshi, Norihiro, Stanton, Lawrence W., Dunn, N. Ray
Format Journal Article
LanguageEnglish
Published Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.04.2012
Subjects
Activin
Activins - metabolism
Animals
BMP
Bone Morphogenetic Protein 4 - metabolism
Cell Differentiation - physiology
Embryonic stem cells
Embryonic Stem Cells - cytology
Embryonic Stem Cells - metabolism
Endoderm
Endoderm - cytology
Endoderm - growth & development
Endoderm - metabolism
Human
Humans
Mice
Mouse
Pluripotency
Signal Transduction
Online AccessGet full text

Cover

More Information
Summary:Human embryonic stem cells (hESCs) herald tremendous promise for the production of clinically useful cell types for the treatment of injury and disease. Numerous reports demonstrate their differentiation into definitive endoderm (DE) cells, the germ layer from which pancreatic β cells and hepatocytes arise, solely from exposure to a high dose of recombinant Activin/Nodal. We show that combining a second related ligand, BMP4, in combination with Activin A yields 15%–20% more DE as compared with Activin A alone. The addition of recombinant BMP4 accelerates the downregulation of pluripotency genes, particularly SOX2, and results in upregulation of endogenous BMP2 and BMP4, which in turn leads to elevated levels of phospho‐SMAD1/5/8. Combined Activin A and BMP4 treatment also leads to an increase in the expression of DE genes CXCR4, SOX17, and FOXA2 when compared with Activin A addition alone. Comparative microarray studies between DE cells harvested on day 3 of differentiation further reveal a novel set of genes upregulated in response to initial BMP4 exposure. Several of these, including APLNR, LRIG3, MCC, LEPREL1, ROR2, and LZTS1, are expressed in the mouse primitive streak, the site of DE formation. Thus, this synergism between Activin A and BMP4 during the in vitro differentiation of hESC into DE suggests a complex interplay between BMP and Activin/Nodal signaling during the in vivo allocation and expansion of the endoderm lineage. STEM CELLS 2012; 30:631–642
Bibliography:ArticleID:STEM1022
ark:/67375/WNG-W6SF3FVK-2
istex:6F698E61238FBE455EA33ABB15FC6FF359E20223
First published online in STEM CELLSEXPRESS December 29, 2011.
Disclosure of potential conflicts of interest is found at the end of this article.
Author contributions: A.K.K.T., Y.A., and H.C.: conception and design, collection and/or assembly of data, and data analysis and interpretation; K.Y.W.: collection and/or assembly of data and data analysis and interpretation; A.S., Y.P., E.K.T, S.T.W., S.A., and N.T.: collection and/or assembly of data; L.W.S.: conception and design, data analysis and interpretation, and financial support; N.R.D.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing. A.K.K.T. and Y.A. contributed equally to this article.
First published online in S
C
EXPRESS
Telephone: +65‐6407‐0164; Fax: +65‐6464‐2048
December 29, 2011.
TEM
ELLS
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1066-5099
1549-4918
DOI:10.1002/stem.1022