Abstract

The EVs and the Secretome: Challenges and Obstacles with EV-based Therapeutics Development

Mario Gimona, Head of Manufacturing-GMP, Paracelsus Medical University Salzburg

Vesicle-based therapy is increasingly being pursued as a safe, cell-free strategy to combat various immunological, musculoskeletal and neurodegenerative diseases. Extracellular vesicle (EV)-enriched preparations obtained from multipotent mesenchymal stromal cells (MSCs) are of particular interest for therapeutic use since they may convey anti-inflammatory, anti-scarring and cyto-protective activities to the recipient cells and tissues. MSCs secrete a variety of bioactive autocrine and paracrine factors including cytokines, chemokines, extracellular matrix proteases, EVs and growth factors. The MSC-derived secretome is thus a complex mixture of proteins, lipids, macromolecular assemblies and vesicular structures, including various types of EVs. The current knowledge on the dynamic structure of vesicular secretome and its interrelated functions is fragmented and the understanding of the nano- and mesoscale properties is limited. The heterogeneity of the vesicular secretome preparations hampers dose finding, the importance of EV uptake and natural tropism remains to be solved, and technologies to better investigate secretome dynamics and corona/halo formation must be developed. Importantly, activities must be initiated that attempt to quantitatively describe one or more biological activities present in/on EVs that are beneficial in elucidating the complex mode-of-action of the vesicular secretome and to assist in the required dose-finding for pre-clinical and clinical application.