Abstract
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 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 in vitro. Normoxic EVs applied into the AIA model reduced Th17 polarisation and improved Regulatory T cell (Treg):Th17 homeostatic balance. Normoxic EVs present the optimal strategy for broad therapeutic benefit. EVs present an effective novel technology with the potential for cell-free therapeutic translation.
Highlights
Mesenchymal stem cells (MSCs) are a promising therapeutic option owing potential for tissue repair through trilineage differentiation capacity, immunomodulatory properties disrupting T cell proliferation, B cell function and dendritic cell (DCs) maturation and promoting anti-inflammatory responses mediated through macrophage interactions [1].The widespread introduction of stem cell therapies was hindered by inconsistent outcomes at clinical trial and donor variability
Western blot analysis of MSC lysate and extracellular vesicles (EVs) isolated in standard culture conditions (EV-NormO2 ) determined positive detection of Alix, a transferrin receptor binding protein involved in the multivesicular body (MVB) biogenesis and biomolecule trafficking [27]
antigen-induced arthritis (AIA) is driven through CD4+ T-lymphocyte responses leading to synovial leukocyte infiltration [37], in comparison to the more commonly applied collagen-induced arthritis (CIA) model which involves a breach of immune tolerance and generation of systemic polyarticular disease through the production of autoantibodies leading to synovitis [38]
Summary
Mesenchymal stem cells (MSCs) are a promising therapeutic option owing potential for tissue repair through trilineage differentiation capacity, immunomodulatory properties disrupting T cell proliferation, B cell function and dendritic cell (DCs) maturation and promoting anti-inflammatory responses mediated through macrophage interactions [1].The widespread introduction of stem cell therapies was hindered by inconsistent outcomes at clinical trial and donor variability. Mesenchymal stem cells (MSCs) are a promising therapeutic option owing potential for tissue repair through trilineage differentiation capacity, immunomodulatory properties disrupting T cell proliferation, B cell function and dendritic cell (DCs) maturation and promoting anti-inflammatory responses mediated through macrophage interactions [1]. Our group has demonstrated the immunomodulatory capacity of both MSCs and their conditioned medium (CM-MSC) to reduce inflammation in a murine antigen-induced arthritis (AIA) model through enhanced Treg function and restored the Treg:Th17 ratio [2,3]. MSCs convey their immunomodulatory properties through cell-to-cell contact, autocrine responses and paracrine signalling [1], including through secretion of extracellular vesicles (EVs) [4]. EVs are membrane bound particles that carry a cargo of microRNA (miRNA), mRNA, lipid, carbohydrate and protein signals to facilitate intercellular communication [5,6,7,8,9].
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