A roadmap from research to clinical testing of mesenchymal stromal cell exosomes in the treatment of psoriasis

The most clinically trialed cells, mesenchymal stromal cells (MSCs), are now known to mainly exert their therapeutic activity through paracrine secretions, which include exosomes. To mitigate potential regulatory concerns on the scalability and reproducibility in the preparations of MSC exosomes, MSC exosomes were produced using a highly characterized MYC-immortalized monoclonal cell line. These cells do not form tumors in athymic nude mice or exhibit anchorage-independent growth, and their exosomes do not carry MYC protein or promote tumor growth. Unlike intra-peritoneal injections, topical applications of MSC exo-somes in a mouse model of IMQ-induced psoriasis alleviate interleukin (IL)-17, IL-23 and terminal comple-ment complex, C5b9 in psoriatic skin. When applied on human skin explants, fluorescence from covalently labeled fluorescent MSC exosomes permeated and persisted in the stratum corneum for about 24 hours with negligible exit out of the stratum corneum into the underlying epidermis. As psoriatic stratum corneums are uniquely characterized by activated complements and Munro microabscesses, we postulated that topically applied exosomes permeate the psoriatic stratum corneum to inhibit C5b9 complement complex through CD59, and this inhibition attenuated neutrophil secretion of IL-17. Consistent with this, we demonstrated that assembly of C5b9 on purified human neutrophils induced IL-17 secretion and this induction was abro-gated by MSC exosomes, which was in turn abrogated by a neutralizing anti-CD 59 antibody. We thus estab-lished the mechanism of action for the alleviation of psoriatic IL-17 by topically applied exosomes.& COPY; 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Automated summary

The most clinically trialed cells, mesenchymal stromal cells (MSCs), exert their therapeutic activity through paracrine secretions, including exosomes. In this study, MSC exosomes were produced using a monoclonal cell line that does not form tumors or exhibit anchorage-independent growth. Topical application of MSC exosomes in a mouse model of psoriasis reduced inflammatory markers in the skin. The mechanism of action involves the permeation of exosomes through the psoriatic skin to inhibit the complement complex and IL-17 secretion.