Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands.
Maastricht University, MERLN Institute for Technology Inspired Regenerative Medicine, Instructive Biomaterial Engineering, Maastricht, the Netherlands.
Acta Biomater. 2023 Jun;163:275-286. doi: 10.1016/j.actbio.2022.05.019. Epub 2022 May 15.
Cells and their surrounding extracellular matrix (ECM) are engaged in dynamic reciprocity to maintain tissue homeostasis: cells deposit ECM, which in turn presents the signals that define cell identity. This loop of phenotype is obvious for biochemical signals, such as collagens, which are produced by and presented to cells, but the role of biomechanical signals is also increasingly recognised. In addition, cell shape goes hand in hand with cell function and tissue homeostasis. Aberrant cell shape and ECM is seen in pathological conditions, and control of cell shape in micro-fabricated platforms disclose the causal relationship between cell shape and cell function, often mediated by mechanotransduction. In this manuscript, we discuss the loop of phenotype for tendon tissue homeostasis. We describe cell shape and ECM organization in normal and diseased tissue, how ECM composition influences tenocyte shape, and how that leads to the activation of signal transduction pathways and ECM deposition. We further describe the use of technologies to control cell shape to elucidate the link between cell shape and its phenotypical markers and focus on the causal role of cell shape in the loop of phenotype. STATEMENT OF SIGNIFICANCE: The dynamic reciprocity between cells and their surrounding extracellular matrix (ECM) influences biomechanical and biochemical properties of ECM as well as cell function through activation of signal transduction pathways that regulate gene and protein expression. We refer to this reciprocity as Loop of Phenotype and it has been studied and demonstrated extensively by using micro-fabricated platforms to manipulate cell shape and cell fate. In this manuscript, we discuss this concept in tendon tissue homeostasis by giving examples in healthy and pathological tenson tissue. Furthermore, we elaborate this by showing how biomaterials are used to feed this reciprocity to manipulate cell shape and function. Finally, we elucidate the link between cell shape and its phenotypical markers and focus on the activation of signal transduction pathways and ECM deposition.
细胞及其周围的细胞外基质（ECM）通过激活信号转导通路来维持组织内稳态，该通路调节基因和蛋白质的表达，从而参与动态的相互作用：细胞产生 ECM，反过来，ECM 又提供定义细胞特性的信号。这种表型循环对于生化信号（如胶原蛋白）来说是显而易见的，胶原蛋白由细胞产生并呈现给细胞，但生物力学信号的作用也越来越受到重视。此外，细胞形状与细胞功能和组织内稳态密切相关。在病理条件下，细胞形状和 ECM 会发生异常，而在微制造平台上控制细胞形状揭示了细胞形状与细胞功能之间的因果关系，这种关系通常通过机械转导来介导。在本文中，我们讨论了肌腱组织内稳态的表型循环。我们描述了正常和患病组织中的细胞形状和 ECM 组织，ECM 组成如何影响肌腱细胞的形状，以及这如何导致信号转导途径的激活和 ECM 的沉积。我们进一步描述了控制细胞形状的技术的使用，以阐明细胞形状与其表型标志物之间的联系，并着重于细胞形状在表型循环中的因果作用。
细胞与其周围的细胞外基质（ECM）之间的动态相互作用通过激活信号转导途径来影响 ECM 的生物力学和生化特性以及细胞功能，这些信号转导途径调节基因和蛋白质的表达。我们将这种相互作用称为表型循环，并通过使用微制造平台来操纵细胞形状和细胞命运来广泛研究和证明了这一点。在本文中，我们通过健康和病理肌腱组织中的实例讨论了肌腱组织内稳态中的这一概念。此外，我们通过展示如何使用生物材料来促进这种相互作用以操纵细胞形状和功能来详细说明这一点。最后，我们阐明了细胞形状与其表型标志物之间的联系，并着重于信号转导途径的激活和 ECM 的沉积。
