Ph.D Students Kangwon National University, Republic of Korea
Abstract: Idiopathic pulmonary fibrosis (IPF) is a fatal chronic interstitial lung disease (ILD) of unknown etiology and mechanism that causes pathological lung scarring leading to lung stiffness, impaired gas exchange and ultimately premature death. Deubiquitinase (DUB) is an important protease that regulates the degradation of target proteins by modulating ubiquitin signaling and has been implicated in several diseases, including pulmonary fibrosis. USP11 has been reported to promote fibrogenesis by stabilizing the pro-fibrotic protein GREM1, and its significant increase in IPF patient tissues suggests that USP11 could be a key therapeutic target for IPF treatment. However, the role and regulatory mechanisms of USP11 in IPF have not been reported. Here, we aimed to investigate the role of USP11 in the progression of pulmonary fibrosis using human induced pluripotent stem cell (hiPSC)-derived alveolar organoids (AOs). To this end, we generated hiPSC-USP11KO using the CRISPR/Cas9 system and confirmed that the pluripotency status of hiPSC-USP11KO was not altered by genome editing. We also found that the expression of alveolar type 2 (AT2) markers (SFTPC and ABCA3) and alveolar epithelial progenitor cell marker NKX2.1 were decreased corresponding to the decrease of USP11 in hiPSC-USP11KO-derived AOs. Interestingly, the depletion of USP11 resulted in decreased collagen deposition and reduced fibrosis markers both at the protein and mRNA levels following TGF-β treatment to characterize pulmonary fibrosis. Collectively, our study suggests that USP11 might be a potential therapeutic target to mitigate pulmonary fibrosis.
Funding Source: This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (RS-2022-NR067319).
