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    • Celecoxib We became interested in the potential role

    2018-11-06

    We became interested in the potential role of ADF genes and Celecoxib dynamics during osteoblast (OB) differentiation of hMSCs for several reasons. First, actin and microtubules are abundant in osteoblasts (Aubin et al., 1983; Arena et al., 1991). During OB differentiation, cell morphology is found to alter from fibroblast-like to cuboidal morphology; this is accompanied by changes in actin cytoskeleton (Lomri et al., 1987). Second, bone is a tissue that is sensitive to mechanical stimulation. The responses of osteoblastic cells to the applied mechanical forces are transmitted through plasma membrane adhesion molecules and induce alterations in actin cytoskeletal organization (Sakai et al., 2011). Third, some studies have reported that the upstream regulator of ADFs, such as Rho GTPase/Rho-Associated kinase (Rock), extracellular matrix (ECM) components, and adhesion kinases, act as regulators for OB differentiation (Harmey et al., 2004; Hamidouche et al., 2009; Mathews et al., 2012). However, evidence for the direct role of ADFs and dynamic organization of actin in MSCs biology and OB differentiation are not clear (Kawano et al., 2013; Shuang et al., 2013).
    Materials and methods
    Results
    Discussion Actin cytoskeleton undergoes cycles of actin assembly that exists in two states: a monomeric state (globular, G-actin) and a fibrous state (filamentous, F-actin). A variety of actin filament lengths and shapes are established by actin-depolymerizing factors (ADFs) and other actin binding factors that are responsible for changes in structure and morphology of eukaryotic cells under different physiological conditions. Among the ADFs, active Cofilin (non-phosphorylated) and DSTN bind to F-actin without capping and severe the actin filament (F-actin) into monomers free ends actin (G-actin). Polymerization of actin is regulated by a series of kinases, such as GTPase RhoA, RhoA kinase (ROCK), and LIM kinases, which phosphorylates the actin depolymerizing protein Cofilin and stabilizes actin filaments (Lodish et al., 2000). In the present study, we demonstrated that changes in the levels of ADFs lead to changes in viability and OB differentiation of hMSCs. siRNA-mediated knocking down of CFL1 or DSTN enhanced OB differentiation and heterotopic bone formation of hMSCs in vivo. Our results confirm part of the findings in previous related studies (Rodriguez et al., 2004; Sonowal et al., 2013), and fulfil the map where the balance of actin assembly (depolymerization and polymerization) is a regulatory factor for viability and OB differentiation of hMSCs and that these effects are mediated through a number of intracellular signaling pathways (Fig. 7). We observed that changes in actin dynamics induce alterations in cell viability. A number of studies have indicated that factors regulating actin cytoskeleton, can exert regulatory functions on cell proliferation. For example, Cofilin phosphorylation mediates proliferation in response to platelet-derived growth factor (PDGF) in rat aortic smooth muscle cells (Won et al., 2008), and inhibition of Cofilin-1 expression blocks PDGF-induced proliferation in endometrium (Wang et al., 2013). Conversely, ectopic-expression of of ADFs and Cofilin suppress the motility and proliferation of human lung cancer cells (Lee et al., 2005). These results suggest that direct regulation of ADFs and actin reassembly can affect cell proliferation and viability. It is possible that ADFs and actin assembly can exert direct regulation of cell cycle genes. It is also possible that actin reassembly provide mechanical structure for cell division (Warn and Magrath, 1983; Kaji et al., 2003) and the mitotic process (Tsai et al., 2009). ADFs have been reported to regulate cell differentiation in a number of tissues. CFL1 and DSTN are required for ureteric bud branching morphogenesis (Kuure et al., 2010). Conditional deletion of CFL1 in neuronal cells enhances cell differentiation (Bellenchi et al., 2007). In addition, Cofilin and phospho-Cofilin expression are increased in conditions favoring myofibroblast differentiation. Knockdown of CFL1 inhibited collagen gel contraction and reduced myofibroblast differentiation (Pho et al., 2008). Moreover, CFL1 has been reported to be activated at the time of podosome belt assembly during osteoclast differentiation (Blangy et al., 2012). We report that ADFs participate in the regulation of OB differentiation of hMSCs and provide a link between changes in cytoskeleton and lineage specification of hMSCs.