Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.
Laboratory of Cell and Tissue Biology, College of Bioresource Sciences, Nihon University, Fujisawa, Japan.
Mol Biol Cell. 2022 Aug 1;33(9):ar78. doi: 10.1091/mbc.E21-12-0609. Epub 2022 Jun 15.
Cellular differentiation is characterized by changes in cell morphology that are largely determined by actin dynamics. We previously showed that depolymerization of the actin cytoskeleton triggers the differentiation of preadipocytes into mature adipocytes as a result of inhibition of the transcriptional coactivator activity of megakaryoblastic leukemia 1 (MKL1). The extracellular matrix (ECM) influences cell morphology via interaction with integrins, and reorganization of the ECM is associated with cell differentiation. Here we show that interaction between actin dynamics and ECM rearrangement plays a key role in adipocyte differentiation. We found that depolymerization of the actin cytoskeleton precedes disruption and degradation of fibrillar fibronectin (FN) structures at the cell surface after the induction of adipogenesis in cultured preadipocytes. A FN matrix suppressed both reorganization of the actin cytoskeleton into the pattern characteristic of adipocytes and terminal adipocyte differentiation, and these inhibitory effects were overcome by knockdown of integrin α5 (ITGα5). Peroxisome proliferator-activated receptor γ was required for down-regulation of FN during adipocyte differentiation, and MKL1 was necessary for the expression of ITGα5. Our findings suggest that cell-autonomous down-regulation of FN-ITGα5 interaction contributes to reorganization of the actin cytoskeleton and completion of adipocyte differentiation.
细胞分化的特征是细胞形态的变化，而细胞形态的变化在很大程度上取决于肌动蛋白动力学。我们之前的研究表明，肌动蛋白细胞骨架的解聚会触发前脂肪细胞向成熟脂肪细胞分化，这是由于巨核细胞白血病 1 (MKL1) 的转录共激活剂活性受到抑制。细胞外基质 (ECM) 通过与整合素的相互作用影响细胞形态，而 ECM 的重排与细胞分化有关。在这里，我们表明肌动蛋白动力学和 ECM 重排之间的相互作用在脂肪细胞分化中起着关键作用。我们发现，在培养的前脂肪细胞诱导脂肪生成后，肌动蛋白细胞骨架的解聚先于细胞表面纤维连接蛋白 (FN) 结构的破坏和降解。FN 基质抑制了肌动蛋白细胞骨架向脂肪细胞特征性模式的重排和终末脂肪细胞分化，而整合素 α5 (ITGα5) 的敲低克服了这些抑制作用。过氧化物酶体增殖物激活受体 γ (peroxisome proliferator-activated receptor γ，PPARγ) 是脂肪细胞分化过程中 FN 下调所必需的，而 MKL1 是 ITGα5 表达所必需的。我们的研究结果表明，FN-ITGα5 相互作用的细胞自主下调有助于肌动蛋白细胞骨架的重排和脂肪细胞分化的完成。
