Department of Chemical Engineering, Indian Institute of Technology Bombay, Mumbai, India.
National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bellary Road, Bangalore, India.
Acta Biomater. 2021 Nov;135:356-367. doi: 10.1016/j.actbio.2021.08.039. Epub 2021 Aug 29.
Directed cell migration plays a crucial role in physiological and pathological conditions. One important mechanical cue, known to influence cell migration, is the gradient of substrate elastic modulus (E). However, the cellular microenvironment is viscoelastic and hence the elastic property alone is not sufficient to define its material characteristics. To bridge this gap, in this study, we investigated the influence of the gradient of viscous property of the substrate, as defined by loss modulus (G) on cell migration. We cultured human mesenchymal stem cells (hMSCs) on a collagen-coated polyacrylamide gel with constant storage modulus (G) but with a gradient in the loss modulus (G). We found hMSCs to migrate from high to low loss modulus. We have termed this form of directional cellular migration as "Viscotaxis". We hypothesize that the high loss modulus regime deforms more due to creep in the long timescale when subjected to cellular traction. Such differential deformation drives the observed Viscotaxis. To verify our hypothesis, we disrupted the actomyosin contractility with myosin inhibitor blebbistatin and ROCK inhibitor Y27632, and found the directional migration to disappear. Further, such time-dependent creep of the high loss material should lead to lower traction, shorter lifetime of the focal adhesions, and dynamic cell morphology, which was indeed found to be the case. Together, findings in this paper highlight the importance of considering the viscous modulus while preparing stiffness-based substrates for the field of tissue engineering. STATEMENT OF SIGNIFICANCE: While the effect of substrate elastic modulus has been investigated extensively in the context of cell biology, the role of substrate viscoelasticity is poorly understood. This omission is surprising as our body is not elastic, but viscoelastic. Hence, the role of viscoelasticity needs to be investigated at depth in various cellular contexts. One such important context is cell migration. Cell migration is important in morphogenesis, immune response, wound healing, and cancer, to name a few. While it is known that cells migrate when presented with a substrate with a rigidity gradient, cellular behavior in response to viscoelastic gradient has never been investigated. The findings of this paper not only reveal a completely novel cellular taxis or directed migration, it also improves our understanding of cell mechanics significantly.
定向细胞迁移在生理和病理条件下起着至关重要的作用。已知有一个重要的力学线索会影响细胞迁移，那就是基质弹性模量（E）梯度。然而，细胞外环境是粘弹性的，因此，弹性特性本身不足以定义其材料特性。为了弥补这一差距，在本研究中，我们研究了基质粘性特性（由损耗模量（G）定义）梯度对细胞迁移的影响。我们在涂有胶原蛋白的聚丙烯酰胺凝胶上培养人骨髓间充质干细胞（hMSC），使存储模量（G）保持恒定，但损耗模量（G）呈梯度变化。我们发现 hMSC 从高损耗模量区域迁移到低损耗模量区域。我们将这种形式的定向细胞迁移称为“粘向性”。我们假设，在受到细胞牵引力时，高损耗模量区域由于在长时间尺度上的蠕变而发生更大的变形。这种差异变形驱动了观察到的粘向性。为了验证我们的假设，我们用肌球蛋白抑制剂 blebbistatin 和 ROCK 抑制剂 Y27632 破坏肌动球蛋白收缩力，发现定向迁移消失了。此外，高损耗材料的这种时变蠕变应该会导致牵引力降低、粘着点寿命缩短和动态细胞形态，事实确实如此。总之，本文的研究结果强调了在组织工程领域制备基于刚度的基质时，考虑粘性模量的重要性。
尽管在细胞生物学背景下已经广泛研究了基质弹性模量的影响，但基质粘弹性的作用却知之甚少。这种遗漏令人惊讶，因为我们的身体不是弹性的，而是粘弹性的。因此，在各种细胞环境中都需要深入研究粘弹性的作用。一个这样的重要环境就是细胞迁移。细胞迁移在形态发生、免疫反应、伤口愈合和癌症等方面都很重要。虽然已知当细胞遇到具有刚度梯度的基质时会迁移，但细胞对粘弹性梯度的反应从未被研究过。本文的研究结果不仅揭示了一种全新的细胞趋性或定向迁移，还显著提高了我们对细胞力学的理解。
