Hypoxia Mesenchymal Stem Cells-Derived Exosomes Suppress IL-5 and STAT3 Gene Expression in a Calcipotriol-Induced Atopic Dermatitis Mouse Model

Salindri Prawitasari; Fikriya Novita  Sari; Rita Agustina; Reynaldi Suryajaya; Rakha Fahreza

doi:10.30872/jtpc.v10i2.442

Authors

Salindri Prawitasari Chemical and Nanobiotechnology Laboratory, Biotechnology, Agung Putra University, Semarang, Indonesia Author
Fikriya Novita Sari Immunology Laboratory, Biotechnology, Agung Putra University, Semarang, Indonesia Author
Rita Agustina Clinical Stem Cell and Cancer, Biomedical Sciences, Agung Putra University, Semarang, Indonesia Author
Reynaldi Suryajaya Stem Cell Secretome Therapy, Biomedical Sciences, Agung Putra University, Semarang, Indonesia Author
Rakha Fahreza Stem Cell Secretome Therapy, Biomedical Sciences, Agung Putra University, Semarang, Indonesia Author

DOI:

https://doi.org/10.30872/jtpc.v10i2.442

Keywords:

atopic dermatitis, EH-MSCs, IL-5, STAT3, Calcipotriol

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by Th2-mediated immune dysregulation and activation of inflammatory signaling pathways. Hypoxia mesenchymal stem cells-derived exosomes (EH-MSCs) have emerged as a promising cell-free therapeutic approach because of their potent immunomodulatory properties. This study evaluated the effects of EH-MSCs on IL-5 and STAT3 gene expression in a calcipotriol-induced AD mouse model. Thirty female C57BL/6 mice were divided into five groups (n = 6/group): healthy control, AD-like + NaCl, AD-like + dexamethasone, AD-like + EH-MSCs (100 μg/kg body weight), and AD-like + EH-MSCs (200 μg/kg body weight). AD-like lesions were induced by topical calcipotriol, and treatments were administered by subcutaneous injection on days 15 and 19. Relative IL-5 and STAT3 gene expression in dorsal skin tissue was quantified using quantitative real-time polymerase chain reaction (qRT-PCR). Calcipotriol significantly upregulated IL-5 and STAT3 expression compared with healthy controls. EH-MSCs treatment significantly reduced the expression of both genes, with the 200 μg/kg dose producing the greatest suppression of STAT3 (p < 0.05). These findings demonstrate that EH-MSCs attenuate Th2-mediated inflammation and inflammatory signaling, supporting their potential as a novel cell-free therapeutic strategy for atopic dermatitis.

Downloads

Download data is not yet available.

References

[1] C. F. Schuler, L. C. Tsoi, A. C. Billi, P. W. Harms, S. Weidinger, and J. E. Gudjonsson, “Genetic and Immunological Pathogenesis of Atopic Dermatitis,” Journal of Investigative Dermatology, vol. 144, no. 5, pp. 954–968, May 2024, doi: 10.1016/j.jid.2023.10.019.

[2] S. Weidinger et al., “Atopic dermatitis,” Nat. Rev. Dis. Primers, vol. 12, no. 1, p. 36, Jun. 2026, doi: 10.1038/s41572-026-00703-z.

[3] M. Newsom, A. M. Bashyam, E. A. Balogh, S. R. Feldman, and L. C. Strowd, “New and Emerging Systemic Treatments for Atopic Dermatitis,” Drugs, vol. 80, no. 11, pp. 1041–1052, Jul. 2020, doi: 10.1007/s40265-020-01335-7.

[4] C. Hemrajani et al., “Overcoming drug delivery barriers and challenges in topical therapy of atopic dermatitis: A nanotechnological perspective,” Biomedicine & Pharmacotherapy, vol. 147, p. 112633, Mar. 2022, doi: 10.1016/j.biopha.2022.112633.

[5] J.-W. Kim, H. J. Lee, P.-S. Chang, J. M. Lee, and J.-C. Kim, “Hypoxic conditioning induced by CoCl2 enhanced the therapeutic effects of mesenchymal stem cell-derived exosomes on oxazolone-induced atopic dermatitis-like skin lesions in BALB/c mice,” Mol. Immunol., vol. 189, pp. 153–162, Jan. 2026, doi: 10.1016/j.molimm.2025.12.008.

[6] L. Cui, P. Liu, K. Wu, X. Han, and G. Peng, “Targeting the JAK/STAT pathway in atopic dermatitis,” Front. Immunol., vol. 17, Mar. 2026, doi: 10.3389/fimmu.2026.1757562.

[7] B. S. Cho, J. O. Kim, D. H. Ha, and Y. W. Yi, “Exosomes derived from human adipose tissue-derived mesenchymal stem cells alleviate atopic dermatitis,” Stem Cell Res. Ther., vol. 9, no. 1, p. 187, Dec. 2018, doi: 10.1186/s13287-018-0939-5.

[8] L. Bao, H. Zhang, and L. S. Chan, “The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis,” JAKSTAT, vol. 2, no. 3, p. e24137, Jul. 2013, doi: 10.4161/jkst.24137.

[9] S. Prawitasari, D. R. Ayu, R. C. S. Irawan, and A. Prabowo, “Surface Marker Expression and Morphological Alterations in Umbilical Cord-Derived MSCs Over Passages 4 to 9: A Flow Cytometry and Microscopic Analysis,” International Journal of Cell and Biomedical Science, vol. 3, no. 9, pp. 261–269, Oct. 2025, doi: 10.59278/cbs.v3i9.51.

[10] A. Putra, I. Alif, A. Prasetio, and S. Prawitasari, “Comparison of Two Tangential Flow Filtration Methods in Isolating CD63+/CD9+ Mesenchymal Stem Cell Exosome,” 2023.

[11] M. Dominici et al., “Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement,” Cytotherapy, vol. 8, no. 4, pp. 315–317, 2006, doi: 10.1080/14653240600855905.

[12] C. Théry et al., “Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines,” J. Extracell. Vesicles, vol. 7, no. 1, Dec. 2018, doi: 10.1080/20013078.2018.1535750.

[13] K.-O. Shin 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, vol. 9, no. 3, p. 680, Mar. 2020, doi: 10.3390/cells9030680.

[14] J. Lötvall et al., “Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles,” J. Extracell. Vesicles, vol. 3, no. 1, Jan. 2014, doi: 10.3402/jev.v3.26913.

[15] W. Pietka, O. Sundnes, C. Hammarström, M. Zucknick, D. Khnykin, and G. Haraldsen, “Lack of interleukin-33 and its receptor does not prevent calcipotriol-induced atopic dermatitis-like inflammation in mice,” Sci. Rep., vol. 10, no. 1, p. 6451, Apr. 2020, doi: 10.1038/s41598-020-63410-z.

[16] A. B. Fishbein, J. I. Silverberg, E. J. Wilson, and P. Y. Ong, “Update on Atopic Dermatitis: Diagnosis, Severity Assessment, and Treatment Selection,” J. Allergy Clin. Immunol. Pract., vol. 8, no. 1, pp. 91–101, Jan. 2020, doi: 10.1016/j.jaip.2019.06.044.

[17] Y. J. Roh et al., “Adipose tissue-derived exosomes alleviate particulate matter-induced inflammatory response and skin barrier damage in atopic dermatitis-like triple-cell model,” PLoS One, vol. 19, no. 1, p. e0292050, Jan. 2024, doi: 10.1371/journal.pone.0292050.

[18] C. Yue et al., “Atopic dermatitis: pathogenesis and therapeutic intervention,” MedComm (Beijing)., vol. 5, no. 12, Dec. 2024, doi: 10.1002/mco2.70029.

[19] Y. Yamamura, C. Nakashima, and A. Otsuka, “Interplay of cytokines in the pathophysiology of atopic dermatitis: insights from Murin models and human,” Front. Med. (Lausanne)., vol. 11, Mar. 2024, doi: 10.3389/fmed.2024.1342176.

[20] W.-Z. Tang et al., “Extracellular vesicles in atopic dermatitis: unraveling pathogenic mediators and engineering therapeutic vectors,” Front. Immunol., vol. 17, May 2026, doi: 10.3389/fimmu.2026.1846799.

[21] J. Kim et al., “Amelioration of Atopic Dermatitis via Suppression of Th2 Receptor Expression by miR-22-3p and HSP70 in Extracellular Vesicles,” Journal of Allergy and Clinical Immunology, vol. 155, no. 2, p. AB222, Feb. 2025, doi: 10.1016/j.jaci.2024.12.685.

[22] D. Park et al., “Mesenchymal stem cell-derived extracellular vesicles exert Th1-mediated anti-inflammatory effects via miR-146a/NF-κB pathway: comparison with dupilumab in a mouse model of atopic dermatitis,” Stem Cell Res. Ther., vol. 16, no. 1, p. 496, Sep. 2025, doi: 10.1186/s13287-025-04649-z.

[23] J. Wang et al., “Gut probiotic Akkermansia muciniphila -derived extracellular vesicles deliver miR-21-5p to alleviate atopic dermatitis by targeting TLR4 signaling,” Nano Res., vol. 19, no. 3, p. 94908421, Mar. 2026, doi: 10.26599/NR.2026.94908421.

[24] Y. Che-Wen, F.-L. Lin, K.-H. Chen, Y.-P. Cheng, Y.-C. Cheng, and J.-W. Guo, “Transcriptional dysregulation of skin barrier genes in atopic dermatitis and psoriasis: Mechanistic insights and emerging therapeutic strategies,” Biomedicine & Pharmacotherapy, vol. 191, p. 118508, Oct. 2025, doi: 10.1016/j.biopha.2025.118508.

[25] L. Li, L. Chen, C. Zhang, W. Yao, Z. Li, and F. Tian, “Role of the STAT3 Signaling Pathway in Cell Proliferation and Inflammation in Psoriasis and Approaches for Targeted Therapies: A Review,” Medical Science Monitor, vol. 32, Apr. 2026, doi: 10.12659/MSM.952449.

[26] C. Yan et al., “MiR-1294 suppresses ROS-dependent inflammatory response in atopic dermatitis via restraining STAT3/NF-κB pathway,” Cell. Immunol., vol. 371, p. 104452, Jan. 2022, doi: 10.1016/j.cellimm.2021.104452.