National Tsing Hua University, Hsinchu 300044, Republic of China.
Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Republic of China.
ACS Appl Bio Mater. 2023 Nov 20;6(11):4764-4774. doi: 10.1021/acsabm.3c00533. Epub 2023 Oct 20.
Mechanobiology is a cornerstone in physiology. However, its role in biomedical applications remains considerably undermined. In this study, we employed cell membrane vesicles (CMVs), which are currently being used as nanodrug carriers, as tactile cues for mechano-regulation of collective cell behaviors. Gliomas, which are among the most resilient brain tumors and have a low patient survival rate, were used as the cell model. We observed that mechanical responses due to the application of glioma- or microglia-derived CMVs resulted in the doubling of the traction stress of glioma cell collectives with a 10-fold increase in the CMV concentration. Glioma-CMVs constrained cell protrusions and hindered their collective migration, with the migration speed of such cells declining by almost 40% compared to the untreated cells. We speculated that the alteration of collective polarization leads to migration speed changes, and this phenomenon was elucidated using the cellular Potts model. In addition to intracellular force modulation and cytoskeletal reorganization, glioma-CMVs altered drug diffusion within glioma spheroids by downregulating the mechano-signaling protein YAP-1 while also marginally enhancing the associated apoptotic events. Our results suggest that glioma-CMVs can be applied as an adjuvant to current treatment approaches to restrict tumor invasion and enhance the penetration of reagents within tumors. Considering the broad impact of mechano-transduction on cell functions, the regulation of cell mechanics through CMVs can provide a foundation for alternative therapeutic strategies.
力学生物学是生理学的基石。然而，其在生物医学应用中的作用仍然被严重低估。在这项研究中，我们使用细胞膜囊泡（CMVs）作为纳米药物载体，作为机械调节细胞群体行为的触觉线索。我们选择神经胶质瘤作为细胞模型，因为它是最具弹性的脑肿瘤之一，患者存活率低。我们观察到，由于应用神经胶质瘤或小胶质细胞衍生的 CMVs 引起的机械反应导致神经胶质瘤细胞群体的牵引力增加了一倍，而 CMV 浓度增加了 10 倍。神经胶质瘤-CMVs 限制了细胞突起并阻碍了它们的集体迁移，与未经处理的细胞相比，这些细胞的迁移速度下降了近 40%。我们推测，群体极化的改变导致迁移速度的变化，这一现象通过细胞 Potts 模型得到了解释。除了细胞内力调节和细胞骨架重组外，神经胶质瘤-CMVs 通过下调机械信号蛋白 YAP-1 改变了神经胶质瘤球体内部的药物扩散，同时轻微增强了相关的凋亡事件。我们的研究结果表明，神经胶质瘤-CMVs 可作为当前治疗方法的辅助手段，限制肿瘤侵袭并增强肿瘤内试剂的渗透。考虑到机械转导对细胞功能的广泛影响，通过 CMVs 调节细胞力学可以为替代治疗策略提供基础。
