Human respiratory disease research currently lacks in vitro models that recapitulate most of the physiology and architecture of the lung. Furthermore, the complex composition and structure of the lung, as well as anatomical differences between humans and mice, frequently lead to disappointing results applied in vivo. Recent advances in organoid technology include new, sophisticated in vitro culture tools that have stimulated considerable interest due to their potential ability to functionally mimic the organ rather than two-dimensional culture or animal models. Hence, pluripotent stem cell-based organoid studies are emerging as an alternative approach able to recapitulate tissue architecture with remarkable fidelity. Moreover, these biomimetic tissue models can be used to investigate the mechanisms of progression of various diseases. Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are the most severe multifactorial respiratory disorders, characterized by irreversible airflow and progressive disease in elderly people. These diseases exhibit a progressive loss of alveolar type 2 epithelial (AT2) cells and accumulation of macrophages in the alveoli, leading to impaired pulmonary function. Despite recent advances in the study of COPD and IPF, effective treatments are lacking because our understanding of those diseases is hindered by their unknown mechanisms. Thus, in this review, the role of AT2 cells and macrophages is highlighted, along with their cell sources and applications for IPF and COPD modeling.
Animal experiments have been performed to predict toxicity in humans in many fields, including toxicology, medicine, and pharmacology, and have contributed to increasing life expectancy. However, animal testing has been a controversial issue for over 100 years due to ethical concerns, and inter-species differences pose limitations for understanding human responses to toxicity. In recent years, many researchers have developed in vitro and in silico alternatives to using animals (e.g., 3-dimensional [3D] organoid culture, organs-on-a-chip, and advanced computer modeling). In this study, we generated 3D alveolar organoids (AOs) for pulmonary toxicity testing following exposure to chemicals, instead of animal models or two-dimensional culture of a single cell type. After human induced pluripotent stem cells were cultured with differentiation medium corresponding to each step for 14 days in 6-well plates, AOs were generated by forced aggregation and cultured with differentiation medium. The AOs were exposed to acrolein and sodium chromate for 24, 72, and 120 hours, and we determined the cytotoxicity of these chemicals using the MTT assay. Exposure to acrolein and sodium chromate for 24 hours decreased proliferation, but the organoid size did not change considerably. However, long-term exposure to acrolein and sodium chromate significantly decreased the organoid size. These findings suggest that AOs could facilitate acute toxicity assessments based on measurements of cell viability in AOs, as well as sub-chronic toxicity assessments based on measurements of both size and viability.
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