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.
Highlights
Adult bone marrow mesenchymal stem/stromal cells (MSCs) are multipotential stem cells, and have the ability to differentiate into osteoblasts, chondrocytes, tenocytes, neurons, adipocytes, and skeletal myocytes [1,2]
We found that the percentage of EdU positive (EdU+) cells in LPS treatment group was much higher than control group, indicating the ratio of proliferative cells in LPS treatment group is significantly higher than control group (Fig 2C and 2D)
To explore the underlying mechanisms of how Toll-like receptor 4 (TLR4) regulates MSC proliferation and osteogenic differentiation, we examined the involvement of Wingless proteins (Wnt) family member
Summary
Adult bone marrow mesenchymal stem/stromal cells (MSCs) are multipotential stem cells, and have the ability to differentiate into osteoblasts, chondrocytes, tenocytes, neurons, adipocytes, and skeletal myocytes [1,2]. MSCs play an important role in bone remodeling because they can be induced to differentiate into osteoblasts. TLR4 Activation and MSC Proliferation and Osteogenic Differentiation can repair bone defects in animal models [3,4]. In addition to their multipotential plasticity, MSCs play a critical role in regulating immune responses in a manner that depends on their state of activation [5,6]. It is important to reveal the molecular mechanisms that regulate the MSC function including survival, proliferation, differentiation and cytokine secretion
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