Islam Tamanna, Hooper Jacob, Zhang Xiaojun, Garcia Clarissa, Hasan Md Mahedi, Drewry David H, Hossain Mohammad Anwar, Al-Hilal Taslim A
Department of Biomedical Engineering, University of Utah, Salt Lake City, Utah, USA.
Department of Biological Sciences, College of Sciences, University of Texas El Paso, El Paso, Texas 79968, USA.
Biomater Sci. 2025 Sep 4. doi: 10.1039/d5bm00224a.
Directional cell migration by pulmonary arterial cells (PACs) is one of the important features of diseases involving arterial remodeling, such as pulmonary arterial hypertension (PAH), a disease that is often characterized by reduced arterial compliance and increased extracellular matrix (ECM) stiffening. However, there are no therapeutics that can halt the directional cell migration of PACs in PAH. The inability to identify drug targets or drugs against the directional cell migration during PAH pathogenesis stems from an incomplete understanding of the process and a lack of effective translational models for screening of candidate small molecules. Here, for the first time, we introduce a bioengineered platform suitable for screening small molecule inhibitors targeting kinase pathways that are potentially linked to ECM-mediated directed cell migration in PAH. We used a photolithographic technique to develop mechanically patterned hydrogels with alternative stripes of soft and stiff bars representing the alternating stiffness regions of PAH ECM. Employing our bioengineered platform, we demonstrated the directional cell migration capacity of PACs and found that PAH-smooth muscle cells (SMCs) showed the highest ability to migrate from soft-stiff regions. Screening of different kinase inhibitors identified the role of JAK/STAT as a mechanosensor in the PAH-SMC-specific directional cell migration. Our study highlighted the use of a mechanically patterned bioengineering platform to identify new drug targets specific to the machinery involved in directional cell migration in PAH.
肺动脉细胞（PACs）的定向细胞迁移是涉及动脉重塑疾病的重要特征之一，如肺动脉高压（PAH），这种疾病通常表现为动脉顺应性降低和细胞外基质（ECM）硬化增加。然而，目前尚无能够阻止PAH中PACs定向细胞迁移的治疗方法。在PAH发病机制中，无法识别针对定向细胞迁移的药物靶点或药物，这源于对该过程的不完全理解以及缺乏用于筛选候选小分子的有效转化模型。在此，我们首次引入了一个生物工程平台，适用于筛选靶向激酶途径的小分子抑制剂，这些激酶途径可能与PAH中ECM介导的定向细胞迁移有关。我们使用光刻技术开发了具有柔软和坚硬条带交替条纹的机械图案化水凝胶，代表PAH ECM的交替硬度区域。利用我们的生物工程平台，我们证明了PACs的定向细胞迁移能力，并发现PAH平滑肌细胞（SMCs）从软-硬区域迁移的能力最强。对不同激酶抑制剂的筛选确定了JAK/STAT作为PAH-SMC特异性定向细胞迁移中的机械传感器的作用。我们的研究强调了使用机械图案化生物工程平台来识别PAH中定向细胞迁移所涉及机制的新药物靶点。
