Department of Bioengineering, University of Colorado, Denver | Anschutz Medical Campus, USA.
Program in Cell Biology, Department of Pediatrics, National Jewish Health, USA.
Biomater Sci. 2022 Dec 6;10(24):7133-7148. doi: 10.1039/d2bm00827k.
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease that progressively and irreversibly alters the lung parenchyma, eventually leading to respiratory failure. The study of this disease has been historically challenging due to the myriad of complex processes that contribute to fibrogenesis and the inherent difficulty in accurately recreating the human pulmonary environment . Here, we describe a poly(ethylene glycol) PEG hydrogel-based three-dimensional model for the co-culture of primary murine pulmonary fibroblasts and alveolar epithelial cells that reproduces the micro-architecture, cell placement, and mechanical properties of healthy and fibrotic lung tissue. Co-cultured cells retained normal levels of viability up to at least three weeks and displayed differentiation patterns observed during IPF progression. Interrogation of protein and gene expression within this model showed that myofibroblast activation required both extracellular mechanical cues and the presence of alveolar epithelial cells. Differences in gene expression indicated that cellular co-culture induced TGF-β signaling and proliferative gene expression, while microenvironmental stiffness upregulated the expression of genes related to cell-ECM interactions. This biomaterial-based cell culture system serves as a significant step forward in the accurate recapitulation of human lung tissue and highlights the need to incorporate multiple factors that work together synergistically into models of lung biology of health and disease.
特发性肺纤维化（IPF）是一种破坏性肺部疾病，它会逐渐且不可逆转地改变肺部实质，最终导致呼吸衰竭。由于导致纤维化的复杂过程众多，以及准确重现人类肺部环境的固有困难，对这种疾病的研究一直具有挑战性。在这里，我们描述了一种基于聚乙二醇（PEG）水凝胶的三维共培养模型，用于原代鼠肺成纤维细胞和肺泡上皮细胞的共培养，该模型再现了健康和纤维化肺组织的微观结构、细胞位置和机械特性。共培养细胞的存活率至少维持在三周以上，并显示出在 IPF 进展过程中观察到的分化模式。对该模型中的蛋白质和基因表达的检测表明，肌成纤维细胞的激活需要细胞外机械线索和肺泡上皮细胞的存在。基因表达的差异表明，细胞共培养诱导了 TGF-β信号和增殖基因的表达，而微环境硬度上调了与细胞-ECM 相互作用相关基因的表达。这种基于生物材料的细胞培养系统是在准确再现人类肺部组织方面向前迈出的重要一步，强调了需要将协同作用的多个因素纳入健康和疾病肺部生物学模型中。
