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J. Biol. Chem., Vol. 282, Issue 1, 782-791, January 5, 2007

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Wnt2 Coordinates the Commitment of Mesoderm to Hematopoietic, Endothelial, and Cardiac Lineages in Embryoid Bodies^*

Hong Wang, Jennifer B. Gilner, Victoria L. Bautch, Da-Zhi Wang, Brandon J. Wainwright^¶, Suzanne L. Kirby, and Cam Patterson^||1

From the Carolina Cardiovascular Biology Center and Departments of ^||Medicine and Pathology, University of North Carolina, Chapel Hill, North Carolina 27599 and the ^¶Center for Molecular and Cellular Biology, University of Queensland, St. Lucia, Queensland 4072, Australia

Our recent gene expression profiling analyses demonstrated that Wnt2 is highly expressed in Flk1⁺ cells, which serve as common progenitors of endothelial cells, blood cells, and mural cells. In this report, we characterize the role of Wnt2 in mesoderm development during embryonic stem (ES) cell differentiation by creating ES cell lines in which Wnt2 was deleted. Wnt2^-/- embryoid bodies (EBs) generated increased numbers of Flk1⁺ cells and blast colony-forming cells compared with wild-type EBs, and had higher Flk1 expression at comparable stages of differentiation. Although Flk1⁺ cells were increased, we found that endothelial cell and terminal cardiomyocyte differentiation was impaired, but hematopoietic cell differentiation was enhanced and smooth muscle cell differentiation was unchanged in Wnt2^-/- EBs. Later stage Wnt2^-/- EBs had either lower or undetectable expression of endothelial and cardiac genes compared with wild-type EBs. Consistently, vascular plexi were poorly formed and neither beating cardiomyocytes nor -actinin-staining cells were detectable in later stage Wnt2^-/- EBs. In contrast, hematopoietic cell gene expression was upregulated, and the number of hematopoietic progenitor colonies was significantly enhanced in Wnt2^-/- EBs. Our data indicate that Wnt2 functions at multiple stages of development during ES cell differentiation and during the commitment and diversification of mesoderm: as a negative regulator for hemangioblast differentiation and hematopoiesis but alternatively as a positive regulator for endothelial and terminal cardiomyocyte differentiation.

Received for publication, July 12, 2006 , and in revised form, November 10, 2006.

^* This work was supported in part by National Institutes of Health Grants HL 61656, HL 03658, and HL 072347 (to C. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Established Investigator of the American Heart Association and a Burroughs Wellcome Fund Clinician Scientist in Translational Research. To whom correspondence should be addressed: Division of Cardiology and Carolina Cardiovascular Biology Center, 8200 Medical Biomolecular Research Bldg., Chapel Hill, NC 27599-7126. Tel.: 919-843-6477; Fax: 919-843-4585; E-mail: cpatters{at}med.unc.edu.

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