Abstract: Fibrotic lung diseases, including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), encounter substantial challenges in developing effective therapeutic options due to their intricate pathophysiology. Traditional two-dimensional culture systems often fail to recapitulate the intricate architecture and cellular interactions of the human lung. To overcome this limitation, we have established a novel lung fibrotic disease model using human airway organoids cultured in a lung extracellular matrix (LuEM) hydrogel. In this study, we compared the effectiveness of a tissue-specific LuEM hydrogel against the commonly used Matrigel for culturing airway organoids. The LuEM hydrogel preserved the extracellular matrix (ECM) protein composition of native lung tissue. Airway organoids cultured in the LuEM hydrogel exhibited upregulation of genes related to lung development and epithelial cell differentiation, particularly in ciliated cells. When exposed to fibrotic stimuli, organoids in the LuEM hydrogel displayed hallmark features of fibrosis. In contrast to airway organoids cultured in Matrigel, those cultured in LuEM hydrogel demonstrated collagen accumulation and contraction proportional to the degree of fibrosis induction. Moreover, the dramatic increase in gene and protein expression of basal cell and fibrosis markers demonstrates that our organoid model closely mimics the characteristics of lung fibrosis. Our findings demonstrate that the LuEM hydrogel provides an optimal substrate for supporting the growth and differentiation of airway organoids, thereby offering a valuable platform for the study of fibrotic lung diseases. This model holds the potential to deepen our understanding of fibrosis and expedite the development of effective therapeutic strategies.
Funding Source: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government, the Ministry of Science and ICT (MSIT) (No. RS-2021-NR059722) and supported in part by Brain Korea 21(BK21) FOUR program.
