Division of Drug Evaluation, New Drug Development Center, Osong Medical Innovation Foundation, Cheongju-si 28160, Korea.
Division of Intractable Diseases, Department of Chronic Diseases Convergence Research, Korea National Institute of Health, Cheongju-si 28159, Korea.
Int J Mol Sci. 2022 Aug 16;23(16):9211. doi: 10.3390/ijms23169211.
Alveolar organoids (AOs), derived from human pluripotent stem cells (hPSCs) exhibit lung-specific functions. Therefore, the application of AOs in pulmonary disease modeling is a promising tool for understanding disease pathogenesis. However, the lack of immune cells in organoids limits the use of human AOs as models of inflammatory diseases. In this study, we generated AOs containing a functional macrophage derived from hPSCs based on human fetal lung development using biomimetic strategies. We optimized culture conditions to maintain the iMACs (induced hPSC-derived macrophages) AOs for up to 14 days. In lipopolysaccharide (LPS)-induced inflammatory conditions, IL-1β, MCP-1 and TNF-α levels were significantly increased in iMAC-AOs, which were not detected in AOs. In addition, chemotactic factor IL-8, which is produced by mononuclear phagocytic cells, was induced by LPS treatment in iMACs-AOs. iMACs-AOs can be used to understand pulmonary infectious diseases and is a useful tool in identifying the mechanism of action of therapeutic drugs in humans. Our study highlights the importance of immune cell presentation in AOs for modeling inflammatory pulmonary diseases.
肺泡类器官（AOs）来源于人多能干细胞（hPSCs），具有肺特异性功能。因此，AOs 在肺部疾病建模中的应用是一种有前途的工具，可以帮助我们理解疾病的发病机制。然而，类器官中缺乏免疫细胞限制了其作为炎症性疾病模型的应用。在这项研究中，我们使用仿生策略，基于人胎肺发育，从 hPSCs 中生成了具有功能性巨噬细胞的 AOs。我们优化了培养条件，使 iMACs（诱导的 hPSC 衍生的巨噬细胞）AOs 能够维持长达 14 天。在脂多糖（LPS）诱导的炎症条件下，iMAC-AOs 中的 IL-1β、MCP-1 和 TNF-α 水平显著升高，而在 AOs 中则没有检测到这些物质。此外，LPS 处理还诱导了单核吞噬细胞产生趋化因子 IL-8。iMACs-AOs 可用于理解肺部感染性疾病，并且是鉴定人类治疗药物作用机制的有用工具。我们的研究强调了在 AOs 中呈现免疫细胞对于模拟炎症性肺部疾病的重要性。
