Loss of Ubiquitin-Specific Protease 11 Mitigates Pulmonary Fibrosis in Human Pluripotent Stem Cell-Derived Alveolar Organoids.

Abstract

The etiology of chronic and lethal interstitial lung disease, termed idiopathic pulmonary fibrosis (IPF), remains unidentified. IPF induces pathological lung scarring that results in rigidity and impairs gas exchange, eventually resulting in premature mortality. Recent findings indicate that deubiquitinating enzymes play a key role in stabilizing fibrotic proteins and contribute to pulmonary fibrosis. The ubiquitin-specific protease 11 (USP11) promotes pro-fibrotic proteins, and its expression elevated in tissue samples from patients with IPF. Thus, this study aimed to examine the effects of loss of function of USP11 gene on the progression of pulmonary fibrosis by utilizing 3D cell culture alveolar organoids (AOs) that replicate the structure and functions of the proximal and distal airways and alveoli. Here, we applied the CRISPR/Cas9 system to knock out the USP11 gene in human induced pluripotent stem cells (hiPSCs) and then differentiated these hiPSCs into AOs. Loss of USP11 gene resulted in abnormalities in type 2 alveolar epithelial cells in the hiPSC-USP11KO-AOs. Moreover, knock out of the USP11 mitigates pulmonary fibrosis caused by TGF-β in hiPSC-USP11KO-AOs by reducing collagen formation and fibrotic markers, suggesting it has the therapeutic potential to treat IPF patients.