IFN‐γ‐Induced CD317 Tethers Extracellular Vesicles to Mesenchymal Stromal Cells Interfering With Immune Modulation

In spite of the numerous clinical trials conducted on mesenchymal stromal cells and their extracellular vesicles (MSC‐EVs) across a wide range of diseases, the field faces challenges in reaching a consensus on crucial parameters such as source, marker definition, and culture conditions, adding to heterogeneous efficiencies. Nevertheless, there is widespread acceptance of the pro‐inflammatory activation of MSCs with IFN‐γ and TNF‐α to enhance immune modulation. Our study highlights the impact of activation duration on MSC‐EV‐mediated immune modulation of macrophages. Extended activation periods (24 h) revealed elevated levels of IFN‐γ‐induced CD317 on the MSC surface. CD317 is known to tether enveloped viral particles to the cell membrane, impeding viral diffusion and spread. We demonstrated the accumulation of EVs on the MSC cell surface following activation or lentiviral CD317 overexpression. In contrast, CD317 knockdown eliminated the enrichment of EVs on the cell surface, significantly enhancing the MSC‐EV‐mediated immune modulation of macrophages. Considering the pivotal role of IFN‐γ in MSC immune modulation and its inevitable contact in patients, our findings propose CD317 as a potential modulator of MSC‐based therapy efficacy in clinical applications.