Collagen microarchitecture mechanically controls myofibroblast differentiation
Collagen microarchitecture mechanically controls myofibroblast differentiation
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胶原微结构机械地控制肌成纤维细胞分化
DOI：
10.1073/pnas.1919394117
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发表时间：
2020-05-26
影响因子：
11.1
通讯作者：
Fischbach, Claudia
中科院分区：
文献类型：
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作者：
Seo, Bo Ri;Chen, Xingyu;Fischbach, Claudia
I型胶原的微结构改变是创伤愈合和癌症的标志，通常被认为是肌成纤维细胞所致。然而，目前尚不清楚胶原微结构对肌成纤维细胞分化的影响。在这里，我们结合实验和计算方法来研究这一假说，即纤维状胶原网络的微结构机械地调节脂肪基质细胞(ASCs)的肌成纤维细胞分化，而不依赖于体积硬度。通过调节凝胶化温度，在保持凝胶浓度不变的情况下，制备了纤维厚度和孔径可控的胶原凝胶。流变特性和模拟数据表明，与纤维较细、孔洞较小的网络相比，纤维较粗、孔洞较大的网络表现出更大的应变刚性。因此，在纤维较厚的支架中培养的ASCs更具收缩能力，表达肌纤维母细胞标志物，并沉积更多延长的纤维连接蛋白纤维。与肌成纤维细胞分化增强一致，纤维较厚的支架中的ASCs表现出更前血管生成的表型，以收缩依赖的方式促进内皮细胞萌发。我们的发现表明，胶原微结构的改变通过局部调节细胞机械信号来调节肌成纤维细胞的分化和纤维化，而不依赖于胶原量和体积硬度。这些发现对再生医学和抗癌治疗具有重要意义。
Altered microarchitecture of collagen type I is a hallmark of wound healing and cancer that is commonly attributed to myofibroblasts. However, it remains unknown which effect collagen microarchitecture has on myofibroblast differentiation. Here, we combined experimental and computational approaches to investigate the hypothesis that the microarchitecture of fibrillar collagen networks mechanically regulates myofibroblast differentiation of adipose stromal cells (ASCs) independent of bulk stiffness. Collagen gels with controlled fiber thickness and pore size were microfabricated by adjusting the gelation temperature while keeping their concentration constant. Rheological characterization and simulation data indicated that networks with thicker fibers and larger pores exhibited increased strain-stiffening relative to networks with thinner fibers and smaller pores. Accordingly, ASCs cultured in scaffolds with thicker fibers were more contractile, expressed myofibroblast markers, and deposited more extended fibronectin fibers. Consistent with elevated myofibroblast differentiation, ASCs in scaffolds with thicker fibers exhibited a more proangiogenic phenotype that promoted endothelial sprouting in a contractility-dependent manner. Our findings suggest that changes of collagen microarchitecture regulate myofibroblast differentiation and fibrosis independent of collagen quantity and bulk stiffness by locally modulating cellular mechanosignaling. These findings have implications for regenerative medicine and anticancer treatments.