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EMBRYONIC STEM CELLS

Retinoic Acid and Bone Morphogenetic Protein Signaling Synergize to Efficiently Direct Epithelial Differentiation of Human Embryonic Stem Cells

^aDepartment of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin, USA;
^bWiCell Research Institute, Madison, Wisconsin, USA

Key Words. Human embryonic stem cells • Ectodermal differentiation • Epithelial lineages • Retinoic acid • p63

Correspondence: Sean P. Palecek, Ph.D., Department of Chemical and Biological Engineering, University of Wisconsin-Madison, 1415 Engineering Drive, Madison, Wisconsin 53706, USA. Telephone: 608-262-8931; Fax: 608-262-5434; e-mail: palecek{at}engr.wisc.edu

Received June 26, 2007; accepted for publication October 18, 2007.
First published online in STEM CELLS EXPRESS   October 25, 2007.



Human embryonic stem cells (hESCs) can differentiate to various somatic lineages, including stratified squamous epithelia, although the molecular mechanisms of epithelial specification from hESCs currently remain undefined. Here, we demonstrate a novel, stage-specific effect of retinoic acid (RA) on epithelial differentiation of hESCs. RA strongly upregulated expression of keratin 18 and the transcription factor p63, which is involved in epidermal morphogenesis and ectodermal specification, while repressing early neural marker transcription. RA-induced hESCs efficiently differentiated to keratin 14-expressing epithelial cells, although this effect was dependent upon on the context of bone morphogenetic protein signaling. Furthermore, these hESC-derived keratinocytes could be subcultured to obtain relatively pure keratinocyte populations that retained the capacity to terminally differentiate. These findings suggest that RA plays an important role in epithelial differentiation of hESCs.

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