Mesenchymal Stem Cell-Derived Exosomes and Other Extracellular Vesicles as New Remedies in the Therapy of Inflammatory Diseases

Abstract

There is growing evidence that mesenchymal stem cell (MSC)-based immunosuppression was mainly attributed to the effects of MSC-derived extracellular vesicles (MSC-EVs). MSC-EVs are enriched with MSC-sourced bioactive molecules (messenger RNA (mRNA), microRNAs (miRNAs), cytokines, chemokines, immunomodulatory factors) that regulate phenotype, function and homing of immune cells. In this review article we emphasized current knowledge regarding molecular mechanisms responsible for the therapeutic effects of MSC-EVs in attenuation of autoimmune and inflammatory diseases. We described the disease-specific cellular targets of MSC-EVs and defined MSC-sourced molecules, which were responsible for MSC-EV-based immunosuppression. Results obtained in a large number of experimental studies revealed that both local and systemic administration of MSC-EVs efficiently suppressed detrimental immune response in inflamed tissues and promoted survival and regeneration of injured parenchymal cells. MSC-EVs-based anti-inflammatory effects were relied on the delivery of immunoregulatory miRNAs and immunomodulatory proteins in inflammatory immune cells (M1 macrophages, dendritic cells (DCs), CD4+Th1 and Th17 cells), enabling their phenotypic conversion into immunosuppressive M2 macrophages, tolerogenic DCs and T regulatory cells. Additionally, through the delivery of mRNAs and miRNAs, MSC-EVs activated autophagy and/or inhibited apoptosis, necrosis and oxidative stress in injured hepatocytes, neurons, retinal cells, lung, gut and renal epithelial cells, promoting their survival and regeneration.

Anti-Tumor Effects of Exosomes Derived from Drug-Incubated Permanently Growing Human MSC

“…Besides the use of MSC as a transplantable cell system, release of extracellular vesicles (EVs) as cell-free vesicular products, including microvesicles or MSC-derived exosomes, is gaining increased attention for potential clinical applications [ 13 ]. Exosomes represent small particles, approximately 20 to 200nm in diameter, as multivesicular bodies of endocytic origin, released into the extracellular compartment [ 14 ].…”

MiR-223 Derived from Mesenchymal Stem Cell Exosomes Alleviates Acute Graft-Versus-Host Disease

“…Meanwhile, the effects were depending on the number of exosomes absorbed by T cells [31]. Also, miRNA had been previously reported to be closely involved in immunosuppression by MSC-EV [14,32]. These experiments demonstrated that MSC-EVs derived miRNA could exert the immunological effects in the therapy.…”

“…The immunomodulatory effects of MSCs are not always immunosuppressive as it is depending on inflammatory microenvironments [11][12][13]. The immunoregulatory mechanism of MSCs involves the autocrine or paracrine secretion of factors, chemokines, and exosomes [6,14]. To date, several studies have shown that exosomes can simulate almost all the biological functions of MSCs [15][16][17][18].…”

Antiviral effects of miRNAs in extracellular vesicles against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mutations in SARS-CoV-2 RNA virus

“…According to numerous experimental and clinical studies, most MSC-based immunomodulatory functions can be attributed to the immunomodulatory properties of the EVs that they secrete. MSC-EVs are rich in biologically active molecules such as mRNA, miRNA, cytokines, and immune modulators, which regulate the function, phenotype, and viability of immune cells [39]. MSC-EVs with immune regulatory activity are also used to study degenerative, chronic, and infectious diseases.…”

“…Specifically, miR-let-7b-5b, miR-21-5p, miR-92a-3p, miR-24-3p, and miR-181a-5p bind the most targets related to inflammatory responses. [39]. First, MSC-EVs are easier to manipulate and store [42].…”