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.

Keywords: extracellular vesicles; immunomodulation; inflammation; paracrine activity; regenerative medicine; stem cells; tissue injury.

Figure 1

Biogenesis and biological activity of EVs. Two main subtypes of EVs are exosomes and ectosomes (microvesicles) that differ in terms of their biogenesis and secretion. Exosomes are initially formed in MVBs located in the cytoplasm, with the involvement of endosomal pathway and intracellular trafficking of MVBs, that may be either degraded in the lysosomes or may fuse with the plasma membrane, releasing exosomes into the extracellular milieu. Ectosomes are considered to be generally larger than exosomes and are formed through the outward plasma membrane budding and shedding. After release EVs may interact with the recipient cells, delivering their cargo via direct fusion with cell membrane, endocytosis, receptor-ligand interaction or phago/pinocytosis. Consequently, internalization of EV content may lead to the changes in the biological activity of the target cell.

Figure 2

Biological role of EVs in homeostasis and pathophysiology. EVs contain bioactive cargo that is responsible for their multimodal activity. EVs may mimic the properties of their cells of origin and were shown to be paracrine factors that play role in cell-to-cell communication and influence the fate of the target cells in several ways, including e.g. stimulation of angiogenesis, cell survival or modulation of the immune response. EVs may also serve as waste disposal machinery, drug-delivery systems and biomarkers for the diagnostic purposes. An influence of EVs in the development of several diseases has been also reported.

Figure 3

Role of EVs in the regulation of the immune response. Depending on the origin, EVs can contain and deliver a diverse bioactive cargo with immunoregulatory activity, that can influence various cell types and modulate their functional status. It has been demonstrated that EVs may have an impact on many immune-related processes, including regulation of immune system activation status, mediation of anti-bacterial and anti-fungal defence, modulation of anti-tumor response, as well as inhibition of harmful overactivation of the immune system. APC, antigen presenting cells; ICAM-1, intercellular adhesion molecule 1; HSP, heat shock protein; IFN-γ, interferon gamma; LFA-1, lymphocyte function-associated antigen 1; MHC II, major histocompatibility complex class II; MerTK, mer receptor tyrosine kinase; NK cells, natural killer cells; PD-L1, programmed death-ligand 1; TNF-α, tumor necrosis factor alpha; Treg, regulatory T cells.

Figure 4

Therapeutic activity of EVs in different tissues and organs. Depending on a type of tissue/organ as a site of vesicle delivery, EVs they may modulate several cellular processes and signaling pathways in the local environment, leading to the tissue regeneration in the place of injury. 8-OHdG, 8-hydroxyguanosine; ACAN, aggrecan; BCL-2, B-cell CLL/lymphoma 2; CCL3, macrophage inflammatory protein-1 α; Col, collagen; COX2, cyclooxygenase-2; Efna3, ephrin A3; IFN-γ, interferon gamma; ILC2s, type 2 innate lymphoid cells; iNOS, inducible nitric oxide synthase; MMP, metalloproteinase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PGE₂, prostaglandin E2; ROS, reactive oxygen species; TGF-β, transforming growth factor β; TNF-α, tumor necrosis factor alpha; Treg, regulatory T cells; VEGF, vascular endothelial growth factor; αSMA, alpha smooth muscle actin.