Stem cell- derived extracellular vesicles as new tools in regenerative medicine - Immunomodulatory role and future perspectives

Abstract

In the last few decades, the practical use of stem cells (SCs) in the clinic has attracted significant attention in the regenerative medicine due to the ability of these cells to proliferate and differentiate into other cell types. However, recent findings have demonstrated that the therapeutic capacity of SCs may also be mediated by their ability to secrete biologically active factors, including extracellular vesicles (EVs). Such submicron circular membrane-enveloped vesicles may be released from the cell surface and harbour bioactive cargo in the form of proteins, lipids, mRNA, miRNA, and other regulatory factors. Notably, growing evidence has indicated that EVs may transfer their bioactive content into recipient cells and greatly modulate their functional fate. Thus, they have been recently envisioned as a new class of paracrine factors in cell-to-cell communication. Importantly, EVs may modulate the activity of immune system, playing an important role in the regulation of inflammation, exhibiting broad spectrum of the immunomodulatory activity that promotes the transition from pro-inflammatory to pro-regenerative environment in the site of tissue injury. Consequently, growing interest is placed on attempts to utilize EVs in clinical applications of inflammatory-related dysfunctions as potential next-generation therapeutic factors, alternative to cell-based approaches. In this review we will discuss the current knowledge on the biological properties of SC-derived EVs, with special focus on their role in the regulation of inflammatory response. We will also address recent findings on the immunomodulatory and pro-regenerative activity of EVs in several disease models, including in vitro and in vivo preclinical, as well as clinical studies. Finally, we will highlight the current perspectives and future challenges of emerging EV-based therapeutic strategies of inflammation-related diseases treatment.

Biogenesis and delivery of extracellular vesicles: harnessing the power of EVs for diagnostics and therapeutics

“…To this end, significant attention has been devoted to developing camouflage strategies to prevent EV recognition by phagocytes. Introducing molecules such as CD47 or CD24 on tumor cell- or fibroblast-derived EVs shields them from phagocytosis ( Kamerkar et al, 2017 ; Karnas et al, 2023 ). Other molecules like CD31, CD44, or β2-microglobulin are also being tested to enhance phagocytosis evasion further, thus extending the circulation half-life of EVs ( Parada et al, 2021 ).…”

Lipid Metabolism Modulation during SARS-CoV-2 Infection: A Spotlight on Extracellular Vesicles and Therapeutic Prospects

“…Since EVs have the same membrane orientation as cells, they expose on their surface the extracellular domains of transmembrane proteins that can bind to nearby or long-distance targets. These EVs transfer their bioactive cargo to target cells, thereby influencing and altering their behaviors [ 61 ]. Cell communication through EVs can occur through various mechanisms, including, paracrine, juxtacrine, endocrine or autocrine pathways [ 8 ].…”

“…Simultaneously, some efforts should be directed to suppressing or removing EVs that selectively promote disorders but are not beneficial, thereby adding novel therapy options to present therapies. Exosome formation and uptake can be inhibited, according to some studies [ 61 , 144 ]. Some researchers are trying to investigate EVs inhibitors as research tools for investigating EVs biology; however, others have assessed such medications’ inhibitory capability in several illness models [ 143 , 144 ].…”

Cell Type-Specific Extracellular Vesicles and Their Impact on Health and Disease

“…The investigation of CTS-EVs allows for a meticulous dissection of the molecular nuances, offering a targeted understanding of immune dysregulation in MS. Moreover, the bioactive cargo within these EVs, consisting of anti-inflammatory cytokines and neurotrophic factors, presents tailored opportunities for therapeutic modulation, aiming at specific cellular pathways contributing to MS pathogenesis [ 135 , 136 ]. Oligodendrocyte-derived EVs (OD-EVs) have proved to be useful markers of cerebrovascular accidents (strokes).…”