Sox9 modulates cell survival and adipogenic differentiation of multipotent adult rat mesenchymal stem cells
Sox9 modulates cell survival and adipogenic differentiation of multipotent adult rat mesenchymal stem cells
复制标题
DOI：
10.1242/jcs.124305
复制
发表时间：
2013-07
影响因子：
4
通讯作者：
S. Stöckl;R. Bauer;A. Bosserhoff;C. Göttl;J. Grifka;S. Grässel
中科院分区：
文献类型：
--
作者：
S. Stöckl;R. Bauer;A. Bosserhoff;C. Göttl;J. Grifka;S. Grässel
Sox 9是早期软骨形成中的关键转录因子，在分化过程和胚胎发育中具有不同的作用。在这里，我们报告说，Sox 9调节细胞存活，并有助于间充质干细胞（MSC）的承诺，成脂或成骨分化谱系。我们发现Sox 9的活性水平影响成脂分化中关键转录因子C/EBP的表达，并且细胞周期蛋白D1介导未分化的成年骨髓来源的大鼠MSC中成骨标志物骨钙素的表达。将稳定的Sox 9敲低引入未分化的大鼠MSC导致增殖率显著降低和凋亡活性增加。这与p21和细胞周期蛋白D1基因和蛋白表达的显著上调有关，伴随着半胱天冬酶3/7活性的诱导和Bcl-2的抑制。我们观察到Sox 9沉默引起S期进展延迟和p21核定位增加。细胞周期蛋白D1的蛋白质稳定性诱导的Sox 9的情况下，推测作为一个功能的改变p38信号。此外，成脂分化的主要转录因子C/EBP在沉默Sox 9后被抑制。由于C/EBP mRNA的不稳定性增加以及对骨钙素基因表达和蛋白质合成的影响，C/EBP蛋白几乎完全不存在，这表明Sox 9水平的微妙平衡不仅对于祖细胞的适当软骨形成分化是必要的，而且还影响MSC的脂肪形成和可能的成骨分化途径。我们的研究结果确定了Sox 9作为未分化的成年大鼠间充质干细胞的分化，增殖和凋亡之间的重要联系，强调了MSC中精确调节的Sox 9活性的微妙平衡的重要性，不仅对于胚胎发生期间的适当骨骼发育，而且可能对于成年人组织和器官的成功修复和再生。
Summary Sox9 is a key transcription factor in early chondrogenesis with distinct roles in differentiation processes and during embryonic development. Here, we report that Sox9 modulates cell survival and contributes to the commitment of mesenchymal stem cells (MSC) to adipogenic or osteogenic differentiation lineages. We found that the Sox9 activity level affects the expression of the key transcription factor in adipogenic differentiation, C/EBP, and that cyclin D1 mediates the expression of the osteogenic marker osteocalcin in undifferentiated adult bone-marrow-derived rat MSC. Introducing a stable Sox9 knockdown into undifferentiated rat MSC resulted in a marked decrease in proliferation rate and an increase in apoptotic activity. This was linked to a profound upregulation of p21 and cyclin D1 gene and protein expression accompanied by an induction of caspase 3/7 activity and an inhibition of Bcl-2. We observed that Sox9 silencing provoked a delayed S-phase progression and an increased nuclear localization of p21. The protein stability of cyclin D1 was induced in the absence of Sox9 presumably as a function of altered p38 signalling. In addition, the major transcription factor for adipogenic differentiation, C/EBP, was repressed after silencing Sox9. The nearly complete absence of C/EBP protein as a result of increased destabilization of the C/EBP mRNA and the impact on osteocalcin gene expression and protein synthesis, suggests that a delicate balance of Sox9 level is not only imperative for proper chondrogenic differentiation of progenitor cells, but also affects the adipogenic and probably osteogenic differentiation pathways of MSC. Our results identified Sox9 as an important link between differentiation, proliferation and apoptosis in undifferentiated adult rat mesenchymal stem cells, emphasizing the importance of the delicate balance of a precisely regulated Sox9 activity in MSC not only for proper skeletal development during embryogenesis but probably also for successful repair and regeneration of tissues and organs in adults.