Anna (Seo Won) Cho

Background: Atopic dermatitis (AD) is an inflammatory skin condition characterized by pruritus and cutaneous lesions with a 10% lifetime prevalence.¹ Th1 and Th2 cells are upregulated in AD in which Th1 cells activate delayed hypersensitivity reactions while Th2 cells induce B cells to produce IgE antibody for allergic reactions. ^2-3 Current treatments include corticosteroids, immunotherapy and JAK inhibitors, but these show limited management of symptoms and exhibit numerous adverse effects with long-term use. ⁴ Researchers began looking into safer and more efficacious means of treating AD by focusing on mesenchymal stem cells (MSCs) particularly derived from human adipose tissue due to its function in immunomodulation and tissue repair.⁵ However due to MSCs’ short half-life and potential risk of tumor formation, research has now shifted to the secretory properties of MSCs such as exosomes that shuttle various proteins to modulate the activity of recipient cells.⁶

Objective: In this narrative review, we explored the use of MSC derived exosomes (MSC-exosomes) in alleviating AD as a novel cell-free therapy.

Search Methods: An online search in the PubMed database was conducted from 2017 to 2023 using the following keywords: “atopic dermatitis”, “mesenchymal stem cells”, “mesenchymal stem cells derived exosomes”, “T helper cell response”.

Results: Studies indicate that MSC-exosomes alleviate AD in mice by decreasing Th cell activation marked by reduced pro-inflammatory cytokines such as IL-6, IL-1β and TNF-α.⁵ It has been demonstrated that this occurs as exosomes suppress activated T cell population by promoting cell cycle arrest via the p27-CDK2 pathway.⁷ P27 is present in all proliferating cells and inhibits CDK2 from forming a complex with cyclin E that induces transcription leading to G1 arrest.⁷ Exosomes have been shown to upregulate p27 while downregulating CDK2, suggesting this mechanism behind the T cell suppression with MSC-exosomes treatment.⁷ Another study suggests that activated exosomes upregulate IDO1, a protein known to degrade tryptophan generating metabolites called kynurenines that induce apoptotic cell death of T cells.⁸ MSC-exosomes have also been applied clinically in which 2 patients with severe AD who received the treatment had an improved Eczema Area Severity Index score.⁹ The improvement was maintained for months after the treatment in both individuals.⁹ These results shine a light on the usage of MSC-exosomes as a novel cell-free therapy for AD.

Conclusion: Studies have found that MSC-exosomes reduce T cell responses by promoting cell cycle arrest via the p27-CDK2 pathway. Exosomes also upregulate IDO1 protein that induces apoptosis of activated T cells suggesting that MSC-exosomes play a strong role in decreasing Th cell activation that is elevated in AD. MSC-exosomes have been utilized in human models with promising results demonstrating their use as a new therapy for AD. However, controlled studies with a larger sample size in human clinical trials are needed to confirm the efficacy and safety of the agent.

Works Cited:

1. Frazier W, Bhardwaj N. Atopic Dermatitis: Diagnosis and Treatment. Am Fam Physician. 2020;101(10):590-598.
2. Najera J, Hao J. Recent advance in mesenchymal stem cells therapy for atopic dermatitis [published online ahead of print, 2022 Dec 28]. J Cell Biochem. 2022;10.1002/jcb.30365. doi:10.1002/jcb.30365
3. Song JY, Kang HJ, Ju HM, Park A, Park H, Hong JS, Kim CJ, Shim JY, Yu J, Choi J. Umbilical cord-derived mesenchymal stem cell extracts ameliorate atopic dermatitis in mice by reducing the T cell responses. Sci Rep. 2019 Apr 29;9(1):6623. doi: 10.1038/s41598-019-42964-7. PMID: 31036853; PMCID: PMC6488580.
4. Ständer S. Atopic Dermatitis. N Engl J Med. 2021;384(12):1136-1143. doi:10.1056/NEJMra2023911
5. Cho BS, Kim JO, Ha DH, Yi YW. Exosomes derived from human adipose tissue-derived mesenchymal stem cells alleviate atopic dermatitis. Stem Cell Res Ther. 2018;9(1):187. Published 2018 Jul 11. doi:10.1186/s13287-018-0939-5
6. Shin KO, Ha DH, Kim JO, et al. Exosomes from Human Adipose Tissue-Derived Mesenchymal Stem Cells Promote Epidermal Barrier Repair by Inducing de Novo Synthesis of Ceramides in Atopic Dermatitis. Cells. 2020;9(3):680. Published 2020 Mar 10. doi:10.3390/cells9030680
7. Lee S, Kim S, Chung H, Moon JH, Kang SJ, Park CG. Mesenchymal stem cell-derived exosomes suppress proliferation of T cells by inducing cell cycle arrest through p27kip1/Cdk2 signaling. Immunol Lett. 2020;225:16-22. doi:10.1016/j.imlet.2020.06.006
8. Kim J, Lee SK, Jung M, et al. Extracellular vesicles from IFN-γ-primed mesenchymal stem cells repress atopic dermatitis in mice. J Nanobiotechnology. 2022;20(1):526. Published 2022 Dec 10. doi:10.1186/s12951-022-01728-8
9. Park KY, Han HS, Park JW, Kwon HH, Park GH, Seo SJ. Exosomes derived from human adipose tissue-derived mesenchymal stem cells for the treatment of dupilumab-related facial redness in patients with atopic dermatitis: A report of two cases. J Cosmet Dermatol. 2022;21(2):844-849. doi:10.1111/jocd.14153