Abstract

   Mesenchymal stem cells (MSCs) have demonstrated potent immunomodulatory
   properties that have shown promise in the treatment of autoimmune
   diseases, including rheumatoid arthritis (RA). However, the inherent
   heterogeneity of MSCs triggered conflicting therapeutic outcomes,
   raising safety concerns and limiting their clinical application. This
   study aimed to investigate the potential of extracellular vesicles
   derived from human gingival mesenchymal stem cells (GMSC-EVs) as a
   therapeutic strategy for RA. Through in vivo experiments using an
   experimental RA model, our results demonstrate that GMSC-EVs
   selectively homed to inflamed joints and recovered Treg and Th17 cell
   balance, resulting in the reduction of arthritis progression. Our
   investigations also uncovered miR-148a-3p as a critical contributor to
   the Treg/Th17 balance modulation via IKKB/NF-κB signaling orchestrated
   by GMSC-EVs, which was subsequently validated in a model of human
   xenograft versus host disease (xGvHD). Furthermore, we successfully
   developed a humanized animal model by utilizing synovial fibroblasts
   obtained from patients with RA (RASFs). We found that GMSC-EVs impeded
   the invasiveness of RASFs and minimized cartilage destruction,
   indicating their potential therapeutic efficacy in the context of
   patients with RA. Overall, the unique characteristics — including
   reduced immunogenicity, simplified administration, and inherent ability
   to target inflamed tissues — position GMSC-EVs as a viable alternative
   for RA and other autoimmune diseases.

   Keywords: Autoimmunity, Stem cells

   Keywords: Autoimmune diseases, Stem cell transplantation
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   Extracellular vesicles derived from human gingival mesenchymal stem
   cells traffic to inflamed joints and halt cartilage destruction in a
   mouse model of rheumatoid arthritis.

Introduction

   Rheumatoid arthritis (RA) is a common autoimmune disease characterized
   by persistent joint inflammation and destruction of cartilage and bone
   ([63]1, [64]2). An increasing amount of evidence indicates that
   mesenchymal stem cells (MSCs) have the potential to fight against
   autoimmune and inflammatory diseases, including autoimmune arthritis
   ([65]3–[66]10). However, several concerns arise in clinical practice.
   For example, MSC in patients are usually dysfunctional, making
   allogenic MSC transfer the only option, which may trigger immune
   rejection. Moreover, the long-term cell fate of the transferred MSC in
   patients remains largely unclear; there are also common side effects,
   including cellular toxicity and tumorigenesis ([67]11–[68]13). An
   effective immune therapy depends on precise targeting and potent immune
   modulation. Current RA treatment regimens involving immune suppressants
   often require high doses of drugs to show a therapeutic effect in the
   affected joints, doses which often trigger adverse off-target effects
   on normal tissues. The current cell-based therapeutic strategies
   against inflammation often lack homing specificity to the inflamed
   sites, and this limits their applications in the clinic. Developing
   innovative therapeutic approaches that are devoid of cells and
   specifically target RA is of utmost importance.

   Recent studies identified that many cells exert their function through
   extracellular vesicles (EVs). There are 2 main categories of EVs,
   namely ectosomes and exosomes ([69]14, [70]15). Ectosomes, which
   consist of microvesicles, microparticles, and large vesicles ranging
   from approximately 50 nm to 1 μm in diameter, are formed by outward
   budding and separate from the plasma membrane. Exosomes, which have a
   size ranging from 30 to 160 nm, are discharged into the extracellular
   matrix when the fusion of multivesicular bodies (MVB) with the plasma
   membrane occurs ([71]14, [72]16, [73]17). Since there is no agreement
   yet on distinct indicators of EV subcategories, it becomes challenging
   to differentiate between exosomes or microvesicles. Hence, exosomes or
   microvesicles are commonly denoted as small EVs, in accordance with the
   classical references ([74]18–[75]20). According to reports, EVs may