(T1036) Modelling particulate matter interaction in the alveolar niche using a chemically defined multi-cell type organoid system using human induced pluripotent stem cells.
PhD Student University of Nottingham Nottingham, England, United Kingdom
Abstract: Air pollution was responsible for 8.1 million deaths globally in 2021, according to the State of Global Air Report from 2024. It is the world's largest environmental risk factor for exacerbation and disease development such as COPD, asthma, and lung cancer. Currently, the mouse is the primary model in respiratory inhalation research as it provides whole organ data on disease mechanisms but does not mimic the human physiological response. Human stem cell in vitro models focus only on epithelial cells leaving a significant gap in our understanding of cell-cell interaction and disease mechanisms. Our model consists of human induced pluripotent stem cell-derived alveolar type II cells (ATIIs), macrophages, dendritic cells, fibroblasts, and endothelial cells differentiated using chemically defined conditions. This model allows us to portray the alveolar niche and model particulate matter interaction in a more physiologically relevant way. Each cell type was characterised using flow cytometry, qPCR, bulk RNA sequencing, and cell-specific enrichment analysis. Consequently, organoid models were assembled to further understand cell-cell interaction mechanisms, proliferation, and interaction with particulate matter. Single-cell sequencing reveals the preservation of the initial cell populations, maturation, and transdifferentiation into niche-specific cell types, such as neuroendocrine-like cells and more mature ATII and fibroblast-like cells. Acute injury modelling of particulate matter shows an in vivo-like response of the epithelial population leading to transdifferentiation into basal-like cells showing specific markers (KRT5, KRT17, TP63). Additionally, the epithelial-to-mesenchymal transition is exacerbated upon injury due to maintenance and regeneration of the organoids, increased expression of fibroblast maturation markers differentiating into myofibroblasts, and protein expression shows an increase in inflammatory markers linked with lung homeostasis as well as pro and anti-inflammatory markers linked with an immune-specific response, showing macrophage polarisation into M1 and M2 phenotype. This model allows for human-specific modelling of respiratory injury and may be an important platform to identify biomarkers for lung disease exacerbation and prognosis.
Funding Source: Biotechnology and Biological Sciences Research Council
