title: TLR4 Activation Promotes Bone Marrow MSC Proliferation and Osteogenic Differentiation via Wnt3a and Wnt5a Signaling.
abstract: Mesenchymal stem cells (MSCs) from adult bone marrow maintain their self-renewal ability and the ability to differentiate into osteoblast. Thus, adult bone marrow MSCs play a key role in the regeneration of bone tissue. Previous studies indicated that TLR4 is expressed in MSCs and is critical in regulating the fate decision of MSCs. However, the exact functional role and underlying mechanisms of how TLR4 regulate bone marrow MSC proliferation and differentiation are unclear. Here, we found that activated TLR4 by its ligand LPS promoted the proliferation and osteogenic differentiation of MSCs in vitro. TLR4 activation by LPS also increased cytokine IL-6 and IL-1β production in MSCs. In addition, LPS treatment has no effect on inducing cell death of MSCs. Deletion of TLR4 expression in MSCs completely eliminated the effects of LPS on MSC proliferation, osteogenic differentiation and cytokine production. We also found that the mRNA and protein expression of Wnt3a and Wnt5a, two important factors in regulating MSC fate decision, was upregulated in a TLR4-dependent manner. Silencing Wnt3a with specific siRNA remarkably inhibited TLR4-induced MSC proliferation, while Wnt5a specific siRNA treatment significantly antagonized TLR4-induced MSC osteogenic differentiation. These results together suggested that TLR4 regulates bone marrow MSC proliferation and osteogenic differentiation through Wnt3a and Wnt5a signaling. These finding provide new data to understand the role and the molecular mechanisms of TLR4 in regulating bone marrow MSC functions. These data also provide new insight in developing new therapy in bone regeneration using MSCs by modulating TLR4 and Wnt signaling activity.
authors.affiliation: The Third Military Medical University, Chongqing, China.|Department of Orthopaedic Surgery, Kunming General Hospital of Chengdu Military Command, Kunming, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: He
authors.affiliation: The Third Military Medical University, Chongqing, China.|Department of Orthopaedic Surgery, Kunming General Hospital of Chengdu Military Command, Kunming, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Orthopaedic Surgery, Kunming General Hospital of Chengdu Military Command, Kunming, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jin
authors.affiliation: Department of Orthopaedic Surgery, Kunming General Hospital of Chengdu Military Command, Kunming, China.
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Orthopaedic Surgery, Kunming General Hospital of Chengdu Military Command, Kunming, China.
authors.forename: Liangbin
authors.initials: L
authors.lastname: Mei
authors.affiliation: Department of Orthopaedic Surgery, Kunming General Hospital of Chengdu Military Command, Kunming, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000276:immunology; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology* / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D051153:Wnt Proteins / Q000276:immunology; D060449:Wnt Signaling Pathway; D000071818:Wnt-5a Protein; D060509:Wnt3A Protein / Q000276:immunology
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D060509:Wnt3A Protein; C438615:Wnt5a protein, mouse