Therapeutic Effects of Hypoxic and Pro-Inflammatory Priming of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Inflammatory Arthritis

Int J Mol Sci. 2021 Dec 23;23(1):126. doi: 10.3390/ijms23010126.

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.

Keywords: extracellular vesicles; immunomodulation; inflammation; mesenchymal stem cells; rheumatoid arthritis.

MeSH terms

  • Animals
  • Arthritis / immunology*
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Proliferation / physiology
  • Cells, Cultured
  • Cytokines / immunology
  • Extracellular Vesicles / immunology*
  • Humans
  • Hypoxia / immunology*
  • Immunomodulation / immunology
  • Inflammation / immunology*
  • Male
  • Mesenchymal Stem Cells / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Secretome / immunology
  • T-Lymphocytes, Regulatory / immunology
  • Th17 Cells / immunology

Substances

  • Cytokines