Changzhou Key Laboratory of Respiratory Medical Engineering, Institute of Biomedical Engineering and Health Sciences, School of Medical and Health Engineering, Changzhou University, Changzhou 213164, China.
Cells. 2024 Oct 14;13(20):1697. doi: 10.3390/cells13201697.
Severe asthma is characterized by increased cell volume (hypertrophy) and enhanced contractile function (hyperresponsiveness) of the airway smooth muscle cells (ASMCs). The causative relationship and underlying regulatory mechanisms between them, however, have remained unclear. Here, we manipulated the single-cell volume of in vitro cultured human ASMCs to increase from 2.7 to 5.2 and 8.2 × 10 μm as a simulated ASMC hypertrophy by culturing the cells on micropatterned rectangular substrates with a width of 25 μm and length from 50 to 100 and 200 μm, respectively. We found that as the cell volume increased, ASMCs exhibited a pro-contractile function with increased mRNA expression of contractile proteins, increased cell stiffness and traction force, and enhanced response to contractile stimulation. We also uncovered a concomitant increase in membrane tension and Piezo1 mRNA expression with increasing cell volume. Perhaps more importantly, we found that the enhanced contractile function due to cell volume increase was largely attenuated when membrane tension and Piezo1 mRNA expression were downregulated, and an auto-regulatory loop between Piezo1 and YAP mRNA expression was also involved in perpetuating the contractile function. These findings, thus, provide convincing evidence of a direct link between hypertrophy and enhanced contractile function of ASMCs that was mediated via Piezo1 mRNA expression, which may be specifically targeted as a novel therapeutic strategy to treat pulmonary diseases associated with ASMC hypertrophy such as severe asthma.
重度哮喘的特征是气道平滑肌细胞（ASMC）的细胞体积增加（肥大）和收缩功能增强（高反应性）。然而，它们之间的因果关系和潜在的调节机制仍不清楚。在这里，我们通过在宽度为 25μm 的微图案化矩形基底上培养细胞，将体外培养的人 ASMC 的单细胞体积从 2.7 增加到 5.2 和 8.2×10μm，模拟 ASMC 肥大。我们发现，随着细胞体积的增加，ASMC 表现出促收缩功能，收缩蛋白的 mRNA 表达增加，细胞硬度和牵引力增加，对收缩刺激的反应增强。我们还发现，随着细胞体积的增加，膜张力和 Piezo1 mRNA 表达同时增加。也许更重要的是，我们发现，当下调膜张力和 Piezo1 mRNA 表达时，由于细胞体积增加而增强的收缩功能会大大减弱，Piezo1 和 YAP mRNA 表达之间也存在自动调节环，这有助于维持收缩功能。这些发现为 ASMC 肥大和收缩功能增强之间的直接联系提供了令人信服的证据，这种联系是通过 Piezo1 mRNA 表达介导的，可能作为一种治疗与 ASMC 肥大相关的肺部疾病（如重度哮喘）的新型治疗策略。
