Alveolar epithelial cells and microenvironmental stiffness synergistically drive fibroblast activation in three-dimensional hydrogel lung models.
Alveolar epithelial cells and microenvironmental stiffness synergistically drive fibroblast activation in three-dimensional hydrogel lung models.
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DOI：
10.1039/d2bm00827k
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发表时间：
2022-12-06
影响因子：
6.6
通讯作者：
Magin, Chelsea M.
中科院分区：
文献类型：
--
作者：
Caracena, Thomas;Blomberg, Rachel;Hewawasam, Rukshika S.;Fry, Zoe E.;Riches, David W. H.;Magin, Chelsea M.
特发性肺纤维化（IPF）是一种毁灭性的肺部疾病，它会逐渐且不可逆地改变肺实质，最终导致呼吸衰竭。由于导致纤维形成的无数复杂过程以及在体外准确重建人类肺部环境的固有困难，对该疾病的研究历来具有挑战性。在这里，我们描述了一种基于聚乙二醇 PEG 水凝胶的三维模型，用于原代小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结构、细胞放置和机械特性。共培养的细胞在长达至少三周的时间内保持正常水平的活力，并显示出 IPF 进展期间在体内观察到的分化模式。对该模型中蛋白质和基因表达的询问表明，肌成纤维细胞活化需要细胞外机械信号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 TGF-β 信号传导和增殖基因表达，而微环境硬度上调与细胞-ECM 相互作用相关的基因表达。这种基于生物材料的细胞培养系统是在体外准确再现人类肺组织方面向前迈出的重要一步，并强调需要将体内协同作用的多种因素纳入健康和疾病的肺生物学模型中。
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 in vitro. 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 in vivo 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 in vitro and highlights the need to incorporate multiple factors that work together synergistically in vivo into models of lung biology of health and disease.
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DOI：
10.1073/pnas.77.7.4113
发表时间：
1980-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
BRULET, P;BABINET, C;JACOB, F
通讯作者：
JACOB, F
影响因子：
29.4
作者：
Fairbanks, Benjamin D;Schwartz, Michael P;Halevi, Alexandra E;Nuttelman, Charles R;Bowman, Christopher N;Anseth, Kristi S
通讯作者：
Anseth, Kristi S
DOI：
10.1083/jcb.200806067
发表时间：
2009-01-26
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kim Y;Kugler MC;Wei Y;Kim KK;Li X;Brumwell AN;Chapman HA
通讯作者：
Chapman HA
影响因子：
5.9
作者：
Katsura, Hiroaki;Kobayashi, Yoshihiko;Hogan, Brigid L. M.
通讯作者：
Hogan, Brigid L. M.
DOI：
10.1164/rccm.201204-0754oc
发表时间：
2012-11-01
影响因子：
24.7
作者：
Booth, Adam J.;Hadley, Ryan;White, Eric S.
通讯作者：
White, Eric S.