Alveolus lung-chip for studying alveolar niche and lung repair

The integrity of air-blood barrier in lung alveoli is essential for proper lung tissue function. Consequently, disruptions to this barrier contribute to numerous lung pathologies, such as lung fibrosis. While static models exist for studying the biology and function of the air-blood barrier, they lack critical parameters like blood flow and mechanical stretching. To address this, we established an alveolus lung-on-a-chip model using human primary AT2 cells (CD45 neg CD31 neg HT2-280 pos) and HUVEC or HMVEC-L endothelial cells. Both cell types were seeded as monolayers, forming a tight cell barrier. In our model, we observed the differentiation of human AT2 cells into AT1 cells under stretching conditions, a process that is difficult to achieve in static 2D models. These results align with other studies in the field, highlighting the importance of mechanotransduction and endothelium for AT2-to-AT1-differentiation. We also exposed the epithelial cell monolayer to TNFα and IPF cocktail. The treatment induced permeability disturbances in the cell barrier, mimicking the pathology of acute exacerbation (AE) in IPF patients. Thus, this model can be utilized to investigate molecular signaling involved in the AE pathogenesis and new target validation. By incorporating macrophages and fibroblasts to the model, we aim to replicate the native environment of the alveolar niche more closely. This will facilitate the examination of the complex multi-cellular communication and interactions during lung injury and help explore non-scarring lung repair mechanisms.