Lipogenic Lung Fibroblast-derived Extracellular Vesicles Mitigate Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease Pathologies through LAT1-mediated Alveolar Type II Cell Restoration

Abstract

Emerging research has revealed specific cellular aberrations in Chronic Obstructive Pulmonary Disease (COPD), with a particular focus on alveolar type 2 (AT2) cells, which play a pivotal role in the restoration of damaged lung tissue and promotion of normal cellular differentiation. Lipofibroblasts (LipoFBs), which are stromal fibroblasts that house lipid droplets, have been identified in close proximity to AT2 cells and have been demonstrated to support AT2 function. In this study, we present a comprehensive investigation into the therapeutic potential of extracellular vesicles (EVs) derived from LipoFBs (LipoFB-EVs) in COPD treatment. They effectively mitigate key COPD pathologies such as cellular senescence and inflammatory responses in lung epithelial cells. This is achieved by reducing reactive oxygen species (ROS) levels and modulating DNA damage response pathways. Moreover, LipoFB-EVs demonstrate antifibrotic properties by inhibiting TGF-{beta}-induced myofibroblast differentiation, surpassing conventional antifibrotic drugs. They also aid in restoring impaired AT2 stem cells, which are crucial for lung homeostasis, by enhancing their viability, colony-forming ability, and proliferation. Furthermore, we identify the presence of L-type amino acid transporter 1 (LAT1) within LipoFB-EVs, which mediates amino acid uptake, particularly leucine transport, and contributes to the restoration of AT2 cell dysfunction. Importantly, the administration of LipoFB-EVs in murine models of COPD resulted in significant improvements in airway inflammation, remodeling, obstruction, cellular senescence, and alveolar emphysema induced by both short- and long-term CS exposure. Overall, our findings highlight the therapeutic potential of LipoFB-EVs as a novel regenerative therapy for COPD, offering promising avenues for future clinical interventions.