Priming Mesenchymal Stem Cells with Lipopolysaccharide Boosts the Immunomodulatory and Regenerative Activity of Secreted Extracellular Vesicles

• Main Authors: Aina Areny-Balagueró (Author), Marta Camprubí-Rimblas (Author), Elena Campaña-Duel (Author), Anna Solé-Porta (Author), Adrián Ceccato (Author), Anna Roig (Author), John G. Laffey (Author), Daniel Closa (Author), Antonio Artigas (Author)
• Format: Book
• Published: MDPI AG, 2024-10-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/pharmaceutics16101316; 1999-4923
• Keywords: acute lung injury; mesenchymal stem cells; extracellular vesicles; LPS priming; immunomodulation; regeneration; Pharmacy and materia medica; RS1-441
• Source: Pharmaceutics, Vol 16, Iss 10, p 1316 (2024)

<b>Background:</b> Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) have been proposed as an alternative to live-cell administration for Acute Respiratory Distress Syndrome (ARDS). MSC-EVs can be chiefly influenced by the environment to which the MSCs are exposed. Here, lipopolysaccharide (LPS) priming of MSCs was used as a strategy to boost the natural therapeutic potential of the EVs in acute lung injury (ALI). <b>Methods:</b> The regenerative and immunemodulatory effect of LPS-primed MSC-EVs (LPS-EVs) and non-primed MSC-EVs (C-EVs) were evaluated in vitro on alveolar epithelial cells and macrophage-like THP-1 cells. In vivo, ALI was induced in adult male rats by the intrapulmonary instillation of HCl and LPS. Rats (<i>n</i> = 8 to 22/group) were randomized to receive a single bolus (1 × 10⁸ particles) of LPS-EVs, C-EVs, or saline. Lung injury severity was assessed at 72 h in lung tissue and bronchoalveolar lavage. <b>Results:</b> In vitro, LPS-EVs improved wound regeneration and attenuated the inflammatory response triggered by the <i>P. aeruginosa</i> infection, enhancing the M2 macrophage phenotype. In in vivo studies, LPS-EVs, but not C-EVs, significantly decreased the neutrophilic infiltration and myeloperoxidase (MPO) activity in lung tissue. Alveolar macrophages from LPS-EVs-treated animals exhibited a reduced expression of CXCL-1, a key neutrophil chemoattractant. However, both C-EVs and LPS-EVs reduced alveolar epithelial and endothelial permeability, mitigating lung damage. <b>Conclusions:</b> EVs from LPS-primed MSCs resulted in a better resolution of ALI, achieving a greater balance in neutrophil infiltration and activation, while avoiding the complete disruption of the alveolar barrier. This opens new avenues, paving the way for the clinical implementation of cell-based therapies.