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Mechanical cell stimulation has only recently been highlighted for its ability to direct cell function and fate. The development of techniques to apply controlled mechanical stimulation to cells has allowed researchers to examine the effects of forces on cell behavior. These studies have shown that cells, and in particular, stem cells are very sensitive to mechanical stimuli. While the potential impact of mechanical forces has been demonstrated by these studies, there have not been many studies that compare the differing effects of stimulation profiles and methods. Further, molecular mechanosensing mechanisms have not been identified. In this work, we compared the effects of cyclic tensile stretch and fluid flow induced shear on mesenchymal stem cell (MSC) adipogenesis. We also implicated extracellular signal-regulated kinase (ERK) phosphorylation as a molecular mechanism involved in both cases.
To test mechanical control of MSC adipogenesis, C3H10T1/2 murine MSCs were exposed to cyclic equibiaxial tensile stretch at 10% strain or 20 dyne/cm2 of fluid flow induced shear and induced to differentiate. For this, Flexcell FX-5000 cell stretching device and Flexcell Streamer fluid flow devices were used. Interestingly, lipid accumulation, a marker of MSC adipogenesis, was suppressed by both mechanical stretch and flow shear. Also, genetic markers for MSC adipogenic commitment (PPARγ, aP2, and C/EBPα) were down regulated by cell stretch. We observed as a potential mechanotransduction mechanism that both stimulation methods induced significant ERK1/2 phosphorylation in MSCs. Furthermore, both stretch and flow induced mechanical suppression of MSC adipogenesis was deteriorated in the presence of PD98059, an established pharmacological ERK inhibitor. Combined, these results indicate that cell stretch and fluid flow suppress adipogenic commitment and differentiation of MSCs, potentially via the mechanical activation of ERK signaling. While more comparisons of varying regimens are required, our data suggests that both cell stretch and fluid flow have potential to down regulate MSC adipogenesis and may share a similar cell mechanotransduction mechanism such as ERK. Further, inhibiting MSC adipogenesis via mechanical cues may provide new insights for obesity research.
Adviser: Jung Yul Lim