



Severe trauma causes more than 5.8 million deaths worldwide each year, often associated with massive hemorrhages and multiple organ failure (approximately 33% of cases). Rhabdomyolysis, common in these patients, results from the destruction of muscle cells and leads to the release of their contents into the bloodstream. This complication promotes acute kidney injury and liver dysfunction. Currently, no specific treatment exists; management remains primarily symptomatic. Mesenchymal stromal cells (MSCs) are widely used for their immunomodulatory and regenerative properties. Preclinical studies have shown that IL-1ß-preconditioned MSCs can prevent kidney and liver damage and reduce vascular permeability after hemorrhagic shock. Their efficacy relies on the secretion of soluble factors and extracellular vesicles, known as acellular products. A large-scale, clinical-grade production method for these products, based on tangential flow filtration, has been developed. These products exhibit experimentally demonstrated immunomodulatory activity and hepatoprotective effects. Ready to use and easy to store, they represent a promising alternative to cell therapies in emergency settings. The objective of this thesis is to optimize the immunomodulatory and anti-inflammatory properties of these cell-free products by promoting their expression of two key immune tolerance molecules, PD-L1 and HLA-G. We will evaluate the interactions between these optimized products and various immune cells in vitro, and then in vivo in a traumatic hemorrhagic shock model (rat model).

