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EMBRYONIC STEM CELLS: CHARACTERIZATION SERIES

Collagen IV Induces Trophoectoderm Differentiation of Mouse Embryonic Stem Cells

^aDepartment of Medicine and Physiology, Cardiovascular Research Laboratory,
^bDepartment of Molecular, Cellular and Developmental Biology,
^cDepartment of Surgery, Regenerative Bioengineering and Repair Laboratory, University of California Los Angeles, Los Angeles, California, USA

Key Words. Collagen IV • Embryonic stem cells • Extracellular matrix • Trophoblast • Placenta

Correspondence: W. Robb MacLellan, M.D., Cardiovascular Research Laboratory, UCLA School of Medicine, 675 C.E. Young Dr., MRL 3-645, Los Angeles, California 90095-1760, USA. Telephone: 310-825-2556; Fax: 310-206-5777; e-mail: rmaclellan{at}mednet.ucla.edu

Received November 10, 2006; accepted for publication March 7, 2007.
First published online in STEM CELLS EXPRESS   March 15, 2007.



The earliest segregation of lineages in the developing embryo is the commitment of cells to the inner cell mass or the trophoectoderm in preimplantation blastocysts. The exogenous signals that control commitment to a particular cell lineage are poorly understood; however, it has been suggested that extracellular "niche" and extracellular matrix, in particular, play an important role in determining the developmental fate of stem cells. Collagen IV (ColIV) has been reported to direct embryonic stem (ES) cell differentiation to mesodermal lineages in both mouse and human ES cells. To define the effects of ColIV on ES cell differentiation and to identify the resulting heterogeneous cell types, we performed microarray analyses and determined global gene expression. We observed that ColIV induced the expression of mesodermal genes specific to hematopoietic, endothelial, and smooth muscle cells and, surprisingly, also a panel of trophoectoderm-restricted markers. This effect was specific to collagen IV, as no trophoblast differentiation was seen on collagen I, laminin, or fibronectin. Stimulation with basic fibroblast growth factor (FGF) or FGF4 increased the number of trophoectodermal cells. These cells were isolated under clonal conditions and successfully differentiated into a variety of trophoblast derivatives. Interestingly, differentiation of ES cells to trophoblastic lineages was only seen in ES cell lines maintained on embryonic feeder layers and was caudal-type homeobox protein 2 (Cdx2)-dependent, consistent with Cdx2's postulated role in trophoectoderm commitment. Our data suggest that, given the appropriate extracellular stimuli, mouse embryonic stem cells can differentiate into trophoectoderm.

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

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