間葉系幹細胞の骨芽細胞分化におけるアクチン細胞骨格⁻細胞核の力学作用によるYAPの局在制御機構

<p>Mechanotransduction, in which mechanical forces and deformations are converted into biochemical signals to change gene expression, is critical for directing the differentiation of mesenchymal stem cells. A number of studies have indicated that a transcriptional regulator, yes-associated protein (YAP), localization change in course of the differentiation is a key for efficient osteogenic differentiation, however the detailed mechanism remains unclear. Here, we hypothesized that YAP localization is regulated by the mechanical interaction between actin cytoskeleton and nucleus, and the changes in the mechanical interaction at the right differentiation points underlie precise osteogenic differentiation. We analyzed the relationship among the three-dimensional morphologies of the actin and the nucleus, and nuclear-cytoplasmic localization of YAP based on the fluorescence images acquired in course of osteogenic differentiation. From undifferentiated to early stage of the differentiation, thick actin bundles were developed on the top of the nucleus, and nuclear height was decreased. At this stage, YAP was highly localized in the nucleus, which was suppressed by inhibition of actin polymerization with a pharmaceutical inhibitor. From middle to later stages of the differentiation, thick actin bundles decreased in some cells, and nuclear height tended to be higher than the other stages irrespective of the density of the actin fibers on top of the nucleus. At these stages, YAP nuclear localization was suppressed, which was unaffected by the inhibition of actin polymerization. YAP nuclear localization in the early stage of the osteogenic differentiation will be triggered by compressive forces applied from the actin bundles on the top surface of the nucleus. Then, from the middle to the later stages, suppression of YAP nuclear localization was because of less compressed nucleus, which was due to decrease in the compressive forces on the nucleus from the actin bundles, and probably ensured by the protection of the nuclear deformation.</p>