Abstract
Endosome-derived small extracellular vesicles (EVs), often referred to as exosomes, are produced by almost all, if not all, cell types, and are critical for intercellular communication. They are composed of a lipid bilayer associated with membrane proteins and contain a payload of lipids, proteins and regulatory RNAs that depends on the parental cell physiological condition. By transferring their “cargo”, exosomes can modulate the phenotype of neighboring and distant cells. Stem cells (SC) were widely studied for therapeutic applications regarding their regenerative/reparative potential as well as their immunomodulatory properties. Whether from autologous or allogeneic source, SC beneficial effects in terms of repair and regeneration are largely attributed to their paracrine signaling notably through secreted EVs. Subsequently, SC-derived EVs have been investigated for the treatment of various diseases, including inflammatory skin disorders, and are today fast-track cell-free tools for regenerative/reparative strategies. Yet, their clinical application is still facing considerable challenges, including production and isolation procedures, and optimal cell source. Within the emerging concept of “allogeneic-driven benefit” for SC-based therapies, the use of EVs from allogeneic sources becomes the pragmatic choice although a universal allogeneic cell source is still needed. As a unique temporary organ that ensures the mutual coexistence of two allogeneic organisms, mother and fetus, the human placenta offers a persuasive allogeneic stem cell source for development of therapeutic EVs. Advancing cell-free therapeutics nurtures great hope and provides new perspectives for the development of safe and effective treatment in regenerative/reparative medicine and beyond. We will outline the current state of the art in regard of EVs, summarize their therapeutic potential in the context of skin inflammatory disorders, and discuss their translational advantages and hurdles.
Highlights
The last three decades have witnessed a wealth of studies to provide the proof-ofconcept in stem cells (SC)-based regenerative strategies to manage diseases that cannot be treated
We summarize the current knowledge about SC-derived extracellular vesicles (EVs) and their potential to promote immunomodulation and re-epithelialization in the context of chronic skin inflammation and wound healing
The efficiency of SCs-derived EVs/Exs in reducing scar formation at the end of wound healing have been suggested by several in vivo experimental models. These EVs/Exs are capable of favoring proper remodeling of ECM and scarring reduction by controlling collagen I and III production and deposition, matrix metalloproteinase-1 (MMP-1) expression, and inhibiting the transforming growth factor-B/SMAD2 pathway to promote the differentiation of fibroblasts into myofibroblasts [63,74]. miRNAs, like miR-21, -23a, -125b, and -145, within the EVs/Exs “cargo” have been implicated in reduction of scar formation and opened the perspective of using EVs/Exs enriched with such miRNAs to enhance the scarring process
Summary
The last three decades have witnessed a wealth of studies to provide the proof-ofconcept in stem cells (SC)-based regenerative strategies to manage diseases that cannot be treated. EVs/Exs from fetal SC express PD-L1 and mediate T cell suppression by inhibiting the CD3-zeta and JAK3 pathway [42], which is critical for T cell proliferation in response to antigen receptor cross-linking Together these findings strongly supported the active contribution of EVs/Exs to the immunoregulatory/anti-inflammatory properties of adult and fetal SCs. Interestingly, inflammation, often marking degenerative disorders and tissue injury, seems to reinforce the immunomodulatory/suppressive capacity of SCs-derived EVs/Exs. MSC treated with IFNγ and TNFα produce EVs/Exs with higher immunosuppressive/antiinflammatory capacity directing the differentiation of M1 macrophages (pro-inflammatory) into an M2 (anti-inflammatory) phenotype with IL-10 production [43]. EVs/Exs from preconditioned SC show higher capacity to induce proliferation, migration, and angiogenesis promoting accelerated wound healing both in in vitro and in vivo experimental models [72,73]
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