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EMBRYONIC STEM CELLS

Activin Alters the Kinetics of Endoderm Induction in Embryonic Stem Cells Cultured on Collagen Gels

^aThe Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;
^bDepartment of Chemical and Biochemical Engineering, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA

Key Words. Activin • Endoderm • Collagen gel • Embryonic stem cells (mouse) • Follistatin • Epiblast

Correspondence: Martin L. Yarmush, M.D., Ph.D., The Center for Engineering in Medicine, 114 16th Street, Room 1402, Charlestown, Massachusetts 02129-4404, USA. Telephone: 617-371-4882 or 617-726-3474; Fax: 617-573-9471; e-mail: ireis{at}sbi.org

Received April 24, 2007; accepted for publication November 23, 2007.
First published online in STEM CELLS EXPRESS   December 6, 2007.



Embryonic stem cell-derived endoderm is critical for the development of cellular therapies for the treatment of disease such as diabetes, liver cirrhosis, or pulmonary emphysema. Here, we describe a novel approach to induce endoderm from mouse embryonic stem (mES) cells using fibronectin-coated collagen gels. This technique results in a homogeneous endoderm-like cell population, demonstrating endoderm-specific gene and protein expression, which remains committed following in vivo transplantation. In this system, activin, normally an endoderm inducer, caused an 80% decrease in the Foxa2-positive endoderm fraction, whereas follistatin increased the Foxa2-positive endoderm fraction to 78%. Our work suggests that activin delays the induction of endoderm through its transient precursors, the epiblast and mesendoderm. Long-term differentiation displays a twofold reduction in hepatic gene expression and threefold reduction in hepatic protein expression of activin-treated cells compared with follistatin-treated cells. Moreover, subcutaneous transplantation of activin-treated cells in a syngeneic mouse generated a heterogeneous teratoma-like mass, suggesting that these were a more primitive population. In contrast, follistatin-treated cells resulted in an encapsulated epithelial-like mass, suggesting that these cells remained committed to the endoderm lineage. In conclusion, we demonstrate a novel technique to induce the direct differentiation of endoderm from mES cells without cell sorting. In addition, our work suggests a new role for activin in induction of the precursors to endoderm and a new endoderm-enrichment technique using follistatin.

Disclosure of potential conflicts of interest is found at the end of this article.