title: 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.
abstract: 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-kappaB. 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.
authors.affiliation: KMEB Laboratory, Medical Biotechnology Center, Odense University Hospital, Southern Denmark University, DK-5000 Odense, Denmark. babdallah@health.sdu.dk
authors.forename: Basem M
authors.initials: BM
authors.lastname: Abdallah
authors.forename: Patrice
authors.initials: P
authors.lastname: Boissy
authors.forename: Qihua
authors.initials: Q
authors.lastname: Tan
authors.forename: Jesper
authors.initials: J
authors.lastname: Dahlgaard
authors.forename: Gunnhildur A
authors.initials: GA
authors.lastname: Traustadottir
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kupisiewicz
authors.forename: Jorge
authors.initials: J
authors.lastname: Laborda
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Delaisse
authors.forename: Moustapha
authors.initials: M
authors.lastname: Kassem
mesh_terms: D017667:Adipocytes / Q000166:cytology; D001402:B-Lymphocytes / Q000276:immunology; D001854:Bone Marrow Cells / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D016207:Cytokines / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000502:physiology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000166:cytology
chemical_list: D002135:Calcium-Binding Proteins; D016207:Cytokines; C512941:DLK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016328:NF-kappa B