Simpson Aryssa, Krissanaprasit Abhichart, Chester Daniel, Koehler Cynthia, LaBean Thomas H, Brown Ashley C
Joint Department of Biomedical Engineering of University of North Carolina - Chapel Hill and North Carolina State University, Raleigh, North Carolina, USA.
Department of Materials Science and Engineering, North Carolina State University, Raleigh, North Carolina, USA.
Wound Repair Regen. 2024 May-Jun;32(3):234-245. doi: 10.1111/wrr.13168. Epub 2024 Mar 9.
Cells integrate many mechanical and chemical cues to drive cell signalling responses. Because of the complex nature and interdependency of alterations in extracellular matrix (ECM) composition, ligand density, mechanics, and cellular responses it is difficult to tease out individual and combinatorial contributions of these various factors in driving cell behavior in homeostasis and disease. Tuning of material viscous and elastic properties, and ligand densities, in combinatorial fashions would enhance our understanding of how cells process complex signals. For example, it is known that increased ECM mechanics and transforming growth factor beta (TGF-β) receptor (TGF-β-R) spacing/clustering independently drive TGF-β signalling and associated myofibroblastic differentiation. However, it remains unknown how these inputs orthogonally contribute to cellular outcomes. Here, we describe the development of a novel material platform that combines microgel thin films with controllable viscoelastic properties and DNA origami to probe how viscoelastic properties and nanoscale spacing of TGF-β-Rs contribute to TGF-β signalling and myofibroblastic differentiation. We found that highly viscous materials with non-fixed TGF-β-R spacing promoted increased TGF-β signalling and myofibroblastic differentiation. This is likely due to the ability of cells to better cluster receptors on these surfaces. These results provide insight into the contribution of substrate properties and receptor localisation on downstream signalling. Future studies allow for exploration into other receptor-mediated processes.
细胞整合多种机械和化学信号以驱动细胞信号转导反应。由于细胞外基质（ECM）组成、配体密度、力学特性以及细胞反应的改变具有复杂的性质和相互依赖性，因此很难梳理出这些不同因素在维持体内稳态和疾病状态下驱动细胞行为的个体和组合作用。以组合方式调节材料的粘性和弹性特性以及配体密度，将增进我们对细胞如何处理复杂信号的理解。例如，已知细胞外基质力学特性的增强和转化生长因子β（TGF-β）受体（TGF-β-R）间距/聚集的增加会独立驱动TGF-β信号转导以及相关的肌成纤维细胞分化。然而，这些输入如何正交地影响细胞结果仍不清楚。在此，我们描述了一种新型材料平台的开发，该平台将具有可控粘弹性的微凝胶薄膜与DNA折纸相结合，以探究TGF-β-R的粘弹性特性和纳米级间距如何影响TGF-β信号转导和肌成纤维细胞分化。我们发现，具有非固定TGF-β-R间距的高粘性材料会促进TGF-β信号转导增强和肌成纤维细胞分化。这可能是由于细胞能够更好地在这些表面上聚集受体。这些结果为底物特性和受体定位对下游信号转导的作用提供了见解。未来的研究可以探索其他受体介导的过程。
