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Published on: July 20, 2019
IFN-γ-Induced CD317 Tethers Extracellular Vesicles to Mesenchymal Stromal Cells Interfering With Immune Modulation
Anton Selich1, Luisa Weisskoeppel1, Ralf Hass2
1Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
Abstract:
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.
Insights
Activating mesenchymal stromal cells (MSCs) with interferon-gamma (IFN-γ) for longer periods increases CD317 expression, which hinders MSC-extracellular vesicle (EV) immune modulation. Reducing CD317 enhances therapeutic efficacy.
Area of Science:
- Immunology
- Cell Biology
- Biotechnology
Background:
- Mesenchymal stromal cells (MSCs) and their extracellular vesicles (EVs) show therapeutic potential but face challenges due to inconsistent parameters.
- Pro-inflammatory activation of MSCs using interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) is widely accepted to enhance immune modulation.
- The impact of activation duration on MSC-EV immune modulation remains underexplored.
Purpose of the Study:
- To investigate the effect of MSC activation duration on MSC-EV-mediated immune modulation of macrophages.
- To elucidate the role of CD317 in MSC-EV accumulation and immune modulation.
Main Methods:
- MSCs were activated with IFN-γ and TNF-α for varying durations.
- Flow cytometry was used to analyze CD317 expression on MSCs.
- EV accumulation on MSC surfaces was assessed after activation or CD317 manipulation (overexpression/knockdown).
- MSC-EV-mediated immune modulation of macrophages was evaluated.
Main Results:
- Extended MSC activation (24 hours) led to increased IFN-γ-induced CD317 expression on the MSC surface.
- CD317 was found to mediate the accumulation of EVs on the MSC cell surface.
- CD317 knockdown eliminated EV surface enrichment and significantly enhanced MSC-EV-mediated immune modulation of macrophages.
Conclusions:
- CD317 acts as a modulator of MSC-EV accumulation on the cell surface.
- Reducing CD317 expression enhances the immune modulatory capacity of MSC-EVs.
- Targeting CD317 could be a strategy to improve the efficacy of MSC-based therapies in clinical settings.
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