Extracellular Vesicle Cargo from Lipofibroblasts Mitigates COPD by Alveolar Type II Cell Restoration

RATIONALE: Emerging research highlights cellular abnormalities in Chronic Obstructive Pulmonary Disease (COPD), focusing on alveolar type 2 (AT2) cells, which are key to lung tissue repair and normal cellular differentiation. Lipofibroblasts (LipoFBs), stromal fibroblasts containing lipid droplets, are closely associated with AT2 cells and support their function. OBJECTIVES: We present a comprehensive investigation into the therapeutic potential of extracellular vesicles (EVs) derived from LipoFBs (LipoFB-EVs) in COPD treatment. METHODS: LipoFBs were induced from lung fibroblasts using Metformin or Rosiglitazone in vitro, and their EVs were isolated via ultracentrifugation for analysis. MAIN RESULTS: 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 anti-fibrotic properties by inhibiting TGF-β-induced myofibroblast differentiation, surpassing conventional anti-fibrotic 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. CONCLUSIONS: Our findings highlight the therapeutic potential of LipoFB-EVs as a novel regenerative therapy for COPD, offering promising avenues for future clinical interventions.