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J. Biol. Chem., Vol. 282, Issue 10, 7339-7351, March 9, 2007

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dlk1/FA1 Regulates the Function of Human Bone Marrow Mesenchymal Stem Cells by Modulating Gene Expression of Pro-inflammatory Cytokines and Immune Response-related Factors^*

Basem M. Abdallah, Recipient of a research fellowship from the Alfred Benzon Foundation in Denmark¹, Patrice Boissy, Qihua Tan^¶, Jesper Dahlgaard^¶, Gunnhildur A. Traustadottir, Katarzyna Kupisiewicz, Jorge Laborda^||, Jean-Marie Delaisse, and Moustapha Kassem

From the KMEB Laboratory, Medical Biotechnology Center, Odense University Hospital, Southern Denmark University, DK-5000 Odense, Denmark, Clinical Cell Biology, Vejle Hospital/Southern Denmark University, DK-7100 Vejle, Denmark, the ^¶Department of Clinical Biochemistry and Genetics, Odense University Hospital, DK-5000 Odense, Denmark, and the ^||Department of Inorganic and Organic Chemistry and Biochemistry, Molecular Biology Branch, Medical School, University of Castilla-La Mancha, 02006 Albacete, Spain

dlk1/FA1 (delta-like 1/fetal antigen-1) is a member of the epidermal growth factor-like homeotic protein family whose expression is known to modulate the differentiation signals of mesenchymal and hematopoietic stem cells in bone marrow. We have demonstrated previously that Dlk1 can maintain the human bone marrow mesenchymal stem cells (hMSC) in an undifferentiated state. To identify the molecular mechanisms underlying these effects, we compared the basal gene expression pattern in Dlk1-overexpressing hMSC cells (hMSC-dlk1) versus control hMSC (negative for Dlk1 expression) by using Affymetrix HG-U133A microarrays. In response to Dlk1 expression, 128 genes were significantly up-regulated (with >2-fold; p < 0.001), and 24% of these genes were annotated as immune response-related factors, including pro-inflammatory cytokines, in addition to factors involved in the complement system, apoptosis, and cell adhesion. Also, addition of purified FA1 to hMSC up-regulated the same factors in a dose-dependent manner. As biological consequences of up-regulating these immune response-related factors, we showed that the inhibitory effects of dlk1 on osteoblast and adipocyte differentiation of hMSC are associated with Dlk1-induced cytokine expression. Furthermore, Dlk1 promoted B cell proliferation, synergized the immune response effects of the bacterial endotoxin lipopolysaccharide on hMSC, and led to marked transactivation of the NF-B. Our data suggest a new role for Dlk1 in regulating the multiple biological functions of hMSC by influencing the composition of their microenvironment "niche." Our findings also demonstrate a role for Dlk1 in mediating the immune response.

Received for publication, August 7, 2006 , and in revised form, November 27, 2006.

^* This work was supported in part by grants from the Danish Medical Research Council, the Novo Nordisk Foundation, the Vellux Foundation, and Danish Center for Stem Cell Research. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1 and 2.

¹ To whom correspondence should be addressed: Dept. of Endocrinology and Metabolism, University Hospital of Odense, Medical Biotechnology Center, Southern Denmark University, DK-5000 Odense C, Denmark. Tel.: 45-65503057; Fax: 45-65503950; E-mail: babdallah{at}health.sdu.dk.

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