Hypoxic and pro-inflammatory priming of mesenchymal stem cell-derived extracellular vesicles to reduce disease severity and immune responses in inflammatory arthritis

Kay, Alasdair G; Treadwell, Kane; Roach, Paul; Morgan, Rebecca; Lodge, Rhys; Hyland, Mairead; Piccinini, Anna M; Forsyth, Nicholas R; Kehoe, Oksana

Abstract

Novel biological therapies have revolutionised the management of Rheumatoid Arthritis (RA) but no cure currently exists. Mesenchymal stem cells (MSCs) immunomodulate inflammatory responses through paracrine signalling, including via secretion of extracellular vesicles (EVs) in the cell secretome. We evaluated the therapeutic potential of hypoxic and pro‐inflammatory primed MSCs‐derived small EVs in an antigen‐induced model of arthritis (AIA). EVs isolated from MSCs cultured normoxically (21% O2, 5% CO2), hypoxically (2% O2, 5% CO2) or with a pro‐inflammatory cytokine cocktail were applied into the AIA model. Disease pathology was assessed post‐arthritis induction through swelling and histopathological analysis of synovial joint structure. Activated CD4+ T cells from healthy mice were cultured with EVs or MSCs to assess deactivation capabilities prior to application of standard EVs in vivo to assess T cell polarisation within the immune response to AIA. All EVs treatments reduced knee‐joint swelling whilst only normoxic and pro‐inflammatory primed EVs improved histopathological outcomes. In vitro culture with EVs did not achieve T cell deactivation. Polarisation towards CD4+ helper cells expressing IL17a (Th17) was reduced when normoxic and hypoxic EV treatments were applied. Normoxic EVs applied into the AIA model reduced Th17 polarisation and restored Th17:Treg homeostatic balance. Priming of MSCs in EV production can be applied to alter the therapeutic efficacy however normoxic EVs present the optimal strategy for broad therapeutic benefit. The varied outcomes observed in MSCs priming may promote EVs optimised for therapies targeted for specific therapeutic priorities. EVs present an effective novel technology with potential for cell‐free therapeutic translation.

• Presentation Conference Type: Poster
• Conference Name: 6th European Congress of Immunology
• Conference Location: Virtual meeting
• Start Date: Sep 1, 2021
• End Date: Sep 4, 2021
• Deposit Date: Jun 23, 2023
• Keywords: Animal models, inflammatory disease, rheumatoid arthritis, stem cells
• Publisher URL: https://onlinelibrary.wiley.com/toc/15214141/2021/51/S1