title: Divergent levels of LBP and TGFβ1 in murine MSCs lead to heterogenic response to TLR and proinflammatory cytokine activation.
abstract: The outstanding heterogeneity of stem cell populations is a major obstacle on the way to their clinical application. It is therefore paramount to identify the molecular mechanisms that underlay this heterogeneity. Individually derived bone marrow mesenchymal stromal cells (MSCs) preparations, studied here, diverged markedly in various properties, despite of being all tripotent in their differentiation potential. Microarray analysis showed that MSC diversity is evident also in highly variable gene expression patterns. Differentially expressed genes were significantly enriched in toll-like receptors (TLRs) and differentiation pathways. Marked differences were observed in LPS binding protein (LBP) and transforming growth factor (TGF)β1 expression. These differences correlated with MSC functionality. Therefore, the possible contribution of these molecules to MSC diversity was examined. In the TLR signaling pathway, LBP levels predicted the ability of specific MSCs to secrete interleukin (IL)-6 in response to LPS. A relatively higher expression of TGFβ1 endowed MSCs with a capacity to respond to IL-1β by reduced osteogenic differentiation. This study thus demonstrates major diversity within MSC isolates, which appears early on following derivation and persists following long-term culture. MSC heterogeneity results from highly variable transcriptome. Differential expression of LBP and TGFβ1, along with other genes, in different MSC preparations, produces the variable responses to external stimuli.
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel, 76100.
authors.forename: Sarit
authors.initials: S
authors.lastname: Levin
authors.forename: Meirav
authors.initials: M
authors.lastname: Pevsner-Fischer
authors.forename: Sivan
authors.initials: S
authors.lastname: Kagan
authors.forename: Hila
authors.initials: H
authors.lastname: Lifshitz
authors.forename: Ada
authors.initials: A
authors.lastname: Weinstock
authors.forename: Diana
authors.initials: D
authors.lastname: Gataulin
authors.forename: Gilgi
authors.initials: G
authors.lastname: Friedlander
authors.forename: Dov
authors.initials: D
authors.lastname: Zipori
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D053583:Interleukin-1beta / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000276:immunology / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D051193:Toll-Like Receptors / Q000819:agonists* / Q000378:metabolism; D059467:Transcriptome; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D051193:Toll-Like Receptors; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D000099231:Lipopolysaccharide-Binding Protein; C508961:Tgfb1 protein, mouse