Laboratory for Cell Biology-Inspired Tissue Engineering, MERLN Institute, University of Maastricht, Maastricht, the Netherlands; BioInterface Science Group, Department of Biomedical Engineering and Institute for Complex Molecular Systems, University of Eindhoven, Eindhoven, the Netherlands.
Laboratory for Cell Biology-Inspired Tissue Engineering, MERLN Institute, University of Maastricht, Maastricht, the Netherlands.
Biomaterials. 2020 Nov;259:120331. doi: 10.1016/j.biomaterials.2020.120331. Epub 2020 Aug 15.
We previously found that surface topographies induce the expression of the Scxa gene, encoding Scleraxis in tenocytes. Because Scxa is a TGF-β responsive gene, we investigated the link between mechanotransduction and TGF-β signaling. We discovered that mesenchymal stem cells exposed to both micro-topographies and TGF-β2 display synergistic induction of SMAD phosphorylation and transcription of the TGF-β target genes SCX, a-SMA, and SOX9. Pharmacological perturbations revealed that Rho/ROCK/SRF signaling is required for this synergistic response. We further found an activation of the early response genes SRF and EGR1 during the early adaptation phase on micro-topographies, which coincided with higher expression of the TGF-β type-II receptor gene. Of interest, PKC activators Prostratin and Ingenol-3, known for inducing actin reorganization and activation of serum response elements, were able to mimic the topography-induced TGF-β response. These findings provide novel insights into the convergence of mechanobiology and TGF-β signaling, which can lead to improved culture protocols and therapeutic applications.
我们之前发现，表面形貌可诱导编码肌腱细胞中的 Scleraxis 的 Scxa 基因的表达。由于 Scxa 是 TGF-β 反应基因，我们研究了力学转导与 TGF-β 信号之间的联系。我们发现，暴露于微形貌和 TGF-β2 的间充质干细胞显示出 SMAD 磷酸化和 TGF-β 靶基因 SCX、a-SMA 和 SOX9 的转录的协同诱导。药理学扰动表明，Rho/ROCK/SRF 信号通路是这种协同反应所必需的。我们进一步发现，在微形貌的早期适应阶段，早期反应基因 SRF 和 EGR1 被激活，这与 TGF-β 型 II 受体基因的更高表达相吻合。有趣的是，PKC 激活剂 Prostratin 和 Ingenol-3，已知可诱导肌动蛋白重排和血清反应元件的激活，能够模拟形貌诱导的 TGF-β 反应。这些发现为力学生物学和 TGF-β 信号的融合提供了新的见解，这可能导致改进的培养方案和治疗应用。
