Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles ameliorate collagen-induced arthritis via immunomodulatory T lymphocytes

Xu, Ke; Ma, Ding; Zhang, Gailian; Gao, Jinfang; Su, Yazhen; Liu, Sumiao; Liu, Yang; Han, Jian; Tian, Mingyi; Chi, Chun‐Wei; Zhang, Liyun

doi:10.1016/j.molimm.2021.04.001

Cited by 23 publications

(14 citation statements)

References 29 publications

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“…For this investigation, the AIA model of inflammatory arthritis is pertinent in investigating the T cell mediated inflammatory response, as AIA is specifically driven through CD4+ T-lymphocyte responses leading to synovial leukocyte infiltration 35 , 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 production of autoantibodies leading to synovitis 36 . Consequently, whilst CIA has recently been applied to evaluate the efficacy of EVs therapies as a model of RA, producing results demonstrating strong immunomodulatory effects with unknown mechanism 19 or indicating T-lymphcyte mechanisms underpin therapeutic outcomes 37 , the AIA model remains appropriate for examining molecular changes evoked through the immunomodulatory action of EVs and their impact upon CD4+ T cells 36 as shown in this study. We aim to inform researchers and clinicians on the efficacy of priming strategies to prepare EVs as an enhanced therapy.…”

Section: Discussionmentioning

confidence: 95%

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

Kay

Treadwell

Roach

et al. 2021

Preprint

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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 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 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.

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Section: Discussionmentioning

confidence: 95%

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

Kay

Treadwell

Roach

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…AIA is specifically 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 ]. Whilst CIA was applied to evaluate the efficacy of EVs therapies as a model of RA, demonstrating strong immunomodulatory effects with unknown mechanism [ 19 ] or indicating T-lymphocyte mechanisms underpin therapeutic outcomes [ 39 ], the AIA model remains appropriate for examining immunomodulatory molecular changes evoked through the action of EVs on CD4+ T cells [ 38 ]. We aim to inform researchers and clinicians on the efficacy of priming strategies to prepare EVs as an enhanced therapy.…”

Section: Discussionmentioning

confidence: 99%

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

Kay

Treadwell

Roach

et al. 2021

IJMS

View full text Add to dashboard Cite

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.

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“…In addition, the differentiation of CD4+IL-17+ cells is affected and the differentiation of T reg CD4+CD25+FoxP3+ is favored. All of the above is accompanied by lower serum levels of IL-17 and an increase in IL-10 and TGF-β [114]. Similarly, the administration of exosomes released by TA-or PL-MSCs in an induced colitis mouse model reduces local and systemic inflammation.…”

Section: Immunoregulation Mediated By Extracellular Vesiclesmentioning

confidence: 98%

TNF-α and IFN-γ Participate in Improving the Immunoregulatory Capacity of Mesenchymal Stem/Stromal Cells: Importance of Cell–Cell Contact and Extracellular Vesicles

López-García

Castro-Manrreza

2021

IJMS

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Mesenchymal stem/stromal cells (MSCs) have an immunoregulatory capacity and have been used in different clinical protocols requiring control of the immune response. However, variable results have been obtained, mainly due to the effect of the microenvironment on the induction, increase, and maintenance of MSC immunoregulatory mechanisms. In addition, the importance of cell–cell contact for MSCs to efficiently modulate the immune response has recently been highlighted. Because these interactions would be difficult to achieve in the physiological context, the release of extracellular vesicles (EVs) and their participation as intermediaries of communication between MSCs and immune cells becomes relevant. Therefore, this article focuses on analyzing immunoregulatory mechanisms mediated by cell contact, highlighting the importance of intercellular adhesion molecule-1 (ICAM-1) and the participation of EVs. Moreover, the effects of tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), the main cytokines involved in MSC activation, are examined. These cytokines, when used at the appropriate concentrations and times, would promote increases in the expression of immunoregulatory molecules in the cell and allow the acquisition of EVs enriched with these molecules. The establishment of certain in vitro activation guidelines will facilitate the design of conditioning protocols to obtain functional MSCs or EVs in different pathophysiological conditions.

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Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles ameliorate collagen-induced arthritis via immunomodulatory T lymphocytes

Cited by 23 publications

References 29 publications

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

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

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

TNF-α and IFN-γ Participate in Improving the Immunoregulatory Capacity of Mesenchymal Stem/Stromal Cells: Importance of Cell–Cell Contact and Extracellular Vesicles

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