Department of Pharmaceutical Sciences , West Virginia University , Morgantown , West Virginia 26506 , United States.
Health Effects Laboratory Division , National Institute for Occupational Safety and Health , Morgantown , West Virginia 26505 , United States.
Nano Lett. 2018 Oct 10;18(10):6500-6508. doi: 10.1021/acs.nanolett.8b03032. Epub 2018 Sep 19.
Fibroblast stem cells or stemlike cells (FSCs) are proposed to play a pivotal role in extracellular matrix (ECM) regeneration by serving as a key source of ECM-producing fibroblasts. We developed a mechanism-based in vitro model for fibrogenicity testing of nanomaterials based on their ability to induce FSCs. Using a FSC-enriched fibroblast focus model to mimic in vivo fibrogenic response, we demonstrated a dose-dependent increase in fibroblast focus formation and collagen production by primary lung fibroblasts treated with multiwalled carbon nanotubes (MWCNTs). The focus-forming cells exhibited stem properties as indicated by stem cell markers expression, sphere formation, and ALDH activity assays. Inhibition of ALDH activity diminished the focus and sphere formation as well as collagen production. In vivo animal studies supported the in vitro findings and indicated the potential utility of FSC-based assays as a rapid screening tool for fibrogenicity testing of nanomaterials. This study also unveils a novel mechanism of nanotube-induced fibrogenesis through ALDH-dependent FSC activation.
成纤维细胞干细胞或类干细胞（FSCs）被认为通过充当产生细胞外基质（ECM）的成纤维细胞的关键来源，在 ECM 再生中发挥关键作用。我们开发了一种基于其诱导 FSCs 能力的纳米材料纤维发生性测试的基于机制的体外模型。使用富含 FSC 的成纤维细胞焦点模型来模拟体内纤维发生反应，我们证明了用多壁碳纳米管（MWCNT）处理的原代肺成纤维细胞中，成纤维细胞焦点形成和胶原蛋白产生呈剂量依赖性增加。焦点形成细胞表现出干细胞特性，如干细胞标志物表达、球体形成和 ALDH 活性测定。ALDH 活性抑制减少了焦点和球体形成以及胶原蛋白产生。体内动物研究支持了体外发现，并表明基于 FSC 的测定作为纳米材料纤维发生性测试的快速筛选工具具有潜在的用途。这项研究还揭示了通过 ALDH 依赖性 FSC 激活诱导纳米管纤维发生的新机制。
