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.

Keywords: extracellular vesicles; immunosuppression; mesenchymal stem cells; regeneration; therapy.

Figure 1

Modulation of phenotype and function of colonic macrophages as the main mechanism for mesenchymal stem cell-derived extracellular vesicle (MSC-EV)-based attenuation of ulcerative colitis: MSC-EVs reduced cleavage of caspase-3, -8 and -9 and alleviated release of damage-associated molecular patterns (DAMPs) from injured gut epithelial cells, resulting in attenuated activation of NF-κB signaling pathway in colon macrophages. Through the delivery of miR-146a, MSC-EVs inhibited TNF receptor-associated factor 6 (TRAF6) and IL-1 receptor-associated kinase 1 (IRAK1) expression, down-regulated phosphorylation of NF-κB p65 and inhibited generation of inflammatory M1 phenotype in macrophages, which was manifested by down-regulated expression of inducible nitric oxide synthase (iNOS), significantly reduced production of nitric oxide (NO), inflammatory cytokines (TNF-α, IL-1β, IL-6) and chemokines (CCL-17 and CCL-24) and resulted in reduced influx of circulating neutrophils, monocytes and lymphocytes in the inflamed gut. Additionally, MSC-EVs induced polarization of colon macrophages in anti-inflammatory M2 phenotype, manifested by increased secretion of immunosuppressive cytokines TGF-β and IL-10 and alleviation of colitis.

Figure 2

Molecular mechanisms responsible for MSC-EVs-based renal protection: MSC-EVs-dependent renal protection during acute kidney injury (AKI) is relied on inhibition of apoptosis, necrosis and oxidative stress and the promotion of autophagy in renal tubular epithelial cells as well as suppression of detrimental immune response. Through the delivery of messenger RNAs (mRNAs), MSC-EVs induce enhanced expression of ERK1/2 and promote survival of proximal tubular epithelial cells (PTEC). MSC-EVs activated autophagy in PTEC and protected against cisplatin-induced AKI by delivering trophic factor 14-3-3ζ, which interacted with ATG-16L, a protein essential for autophagy induction. MSC-EVs enhanced activation of NF-E2-related factor 2/antioxidant responsive element, decreased expression of NADPH oxidase and reduced production of reactive oxygen species in ischemic kidneys and promoted their regeneration. Additionally, through the delivery of miR-21, MSC-EVs significantly attenuated capacity for antigen-presentation of renal dendritic cells, which resulted in reduced activation of Th1 and Th17 cells and alleviation of Th1 and Th17 cell-driven inflammation in the kidneys. Through the delivery of microRNAs (miRNAs), particularly let-7b, MSC-EVs induced conversion of inflammatory M1 macrophages into immunosuppressive M2 cells, which produced lower amount of inflammatory cytokines (TNF-α and IL-1β) and chemokine CXCL1, resulting in alleviated acute and chronic renal inflammation. MSC-sourced miRNA, particularly let-7c, targeted pro-fibrotic genes (collagen IVα1, TGF-β1 and TGFβR1) in inflamed kidneys, crucially contributing to the therapeutic effects of MSC-EVs in renal fibrosis. Additionally, neo-angiogenesis, induced by MSC-derived vascular endothelial growth factor (VEGF) was also responsible for beneficial effects of MSC-EVs in alleviation of renal fibrosis.