Mesenchymal Stem Cell-Derived Extracellular Vesicles as Non-Coding RNA Therapeutic Vehicles in Autoimmune Diseases

Abstract

Autoimmune diseases (ADs) are characterized by the activation of the immune system against self-antigens. More common in women than in men and with an early onset, their incidence is increasing worldwide, and this, combined with their chronic nature, is contributing to an enlarged medical and economic burden. Conventional immunosuppressive agents are designed to alleviate symptoms but do not constitute an effective therapy, highlighting a need to develop new alternatives. In this regard, mesenchymal stem cells (MSCs) have demonstrated powerful immunosuppressive and regenerative effects. MSC-derived extracellular vesicles (MSC-EVs) have shown some advantages, such as less immunogenicity, and are proposed as novel therapies for ADs. In this review, we summarize current perspectives on therapeutic options for ADs based on MSCs and MSC-EVs, focusing particularly on their mechanism of action exerted through their non-coding RNA (ncRNA) cargo. A complete state-of-the-art review was performed, centralized on some of the most severe ADs (rheumatoid arthritis, autoimmune type 1 diabetes mellitus, and systemic lupus erythematosus), giving evidence that a promising field is evolving to overcome the current knowledge and provide new therapeutic possibilities centered on MSC-EVs and their role as ncRNA delivery vehicles for AD gene therapy.

Keywords: autoimmune diseases; exosomes; extracellular vesicles; immunomodulation; mesenchymal stem cells; microRNA; non-coding RNA.

Figure 1

Immunomodulatory and pro-regenerative effects of mesenchymal stem cells (MSC) or MSC-derived extracellular vesicles (MSC-EVs) in autoimmune diseases. MSCs exert effects on T and B lymphocytes, natural killers (NK), dendritic cells (DC), neutrophils and macrophages by direct cell-cell interaction of EVs secretion, protecting and regenerating the damaged cells and mitigating the immune response. Breg: B regulatory cells; IFN: interferon; IL: interleukin; Th1: T helper 1 effector cells; Th2: T helper 2 effector cells; TNF: tumor necrosis factor; Treg: T regulatory cells. Created mainly in biorender.com.

Figure 2

Origin and therapeutic purposes of mesenchymal stem cells (MSC) and MSC-derived exosomes (MSC-Exos). MSCs are found in many tissues, such as lung (L), liver (LH), dental pulp (DP), bone marrow (BM), adipose tissue (AD), umbilical cord (UC) and placenta (P). MSC-Exos play therapeutic roles as drug delivery systems (targeted MSC-exos) for immunomodulation, an-ti-inflammatory effect and tissue regeneration and engineering. Created mainly in biorender.com.

Figure 3

Summary of protective, regenerative or immunomodulatory capabilities of MSC-derived extracellular vesicles (MSC-EVs) administered in experimental models of different ADs. Several studies on non-coding RNA (miRNAs, lncRNA, circRNA and tsRNA) have demonstated their effects and mechanisms as therapeutic systems to ameliorate diabetic peripheral neuropathy, relieve diabetic retinopathy, improve wound healing of diabetic ulcers, attenuate arthritis and exert anti-inflammatory effect in systemic lupus erythematosus (SLE). Arrows indicate activation or induction, T-bars indicate inhibition. Circ: circular RNA; CXCL9: Chemokine (C-X-C motif) ligand 9; IL: interleukin; ITGA1: Integrin Subunit Alpha 1; lncRNA: long non-coding RNA; miRNA: microRNA; MMP4: matrix metalloproteinase 4; MSC: mesenchymal stem cells; PTEN: Phosphatase and tensin homolog; TRL4: Toll-like receptor 4; tsRNA: transfer RNA-derived fragments; VEGF: vascular endothelial growth factor. Created mainly in biorender.com.