In Vitro and Ex Vivo Immunomodulatory Effects of Human Placental Mesenchymal Stem Cells in Hidradenitis Suppurativa

Vaiva Jariene^1,2*Paulius Valiukevicius^3,4Ruta Insodaite^5,6Ugne Janonyte¹Romaldas Maciulaitis⁵Skaidra Valiukeviciene^1,7Astra Vitkauskiene⁸Evelina Zemaite⁸Christos C. Zouboulis^1,10,7,9Justinas Maciulaitis^11,5

• ¹Department of Skin and Venereal Diseases, Lithuanian University of Health Sciences (LSMU), Kaunas, Lithuania
• ²Department of Skin and Venereal Diseases, Hospital of Lithuanian University of Health Sciences Kauno Klinikos, European Reference Network for Rare and Complex Diseases of the Skin (ERN Skin) member, Kaunas, Lithuania
• ³Department of Neurology, Lithuanian University of Health Sciences (LSMU), Kaunas, Lithuania
• ⁴Department of Neurology, Hospital of Lithuanian University of Health Sciences Kauno Klinikos, Kaunas, Lithuania
• ⁵Institute of Physiology and Pharmacology, Lithuanian University of Health Sciences (LSMU), Kaunas, Lithuania
• ⁶Institute of Biology Systems and Genetic Research, Lithuanian University of Health Sciences (LSMU), Kaunas, Lithuania
• ⁷Hospital of Lithuanian University of Health Sciences Kauno Klinikos, European Reference Network for Rare and Complex Diseases of the Skin (ERN Skin) member, Kaunas, Lithuania
• ⁸Department of Laboratory Medicine, Lithuanian University of Health Sciences (LSMU), Kaunas, Lithuania
• ⁹Departments of Dermatology, Venereology, Allergology and Immunology, Staedtisches Klinikum Dessau, European Reference Network for Rare and Complex Diseases of the Skin (ERN- Skin) member, Dessau, Germany
• ¹⁰Brandenburg Medical School Theodor Fontane and Faculty of Health Sciences Brandenburg, Dessau, Germany
• ¹¹Institute of Cardiology, Lithuanian University of Health Sciences (LSMU), Kaunas, Lithuania

Background Hidradenitis suppurativa is a chronic inflammatory skin disease marked by immune dysregulation and elevated pro-inflammatory cytokines. While biologics like adalimumab target specific pathways, their limited efficacy highlights the need for broader immunomodulatory treatments. Mesenchymal stem/stromal cells (MSCs) have shown promise due to their immunosuppressive properties and ability to modulate both innate and adaptive immunity. This study investigates the effects of naïve (n-MSCs) and cytokine-preactivated (a-MSCs) placental MSCs on the immune responses in HS. Methods MSCs were isolated from healthy term placentas and either used naïvely or preactivated with IFN-γ and TNF-α. Peripheral blood mononuclear cells (PBMCs) from HS patients (n=3) and healthy donors (n=3) were co-cultured with n-MSCs, a-MSCs, or adalimumab. Additionally, lesional, perilesional, and healthy 4 mm in diameter skin punch biopsies from 10 HS patients and 3 controls were cultured in a transwell system with the same interventions. Flow cytometry assessed lymphocytes proliferation and T cell subsets while Luminex assays measured cytokine levels. Results Both n-MSCs and a-MSCs significantly inhibited lymphocytes proliferation and shifted T cell populations, increasing CD4+ and decreasing CD8+ T cells. The a-MSCs notably reduced IL-17A and IFN-γ in PBMC co-cultures; n-MSCs had partial effects. HS skin explants exhibited elevated IL-1β, IL-10, and IL-17A compared to healthy skin. The n-MSCs markedly reduced all three cytokines in lesional and perilesional tissues. Moreover, a-MSCs selectively increased IL-10 in lesional skin. Conclusion Placental MSCs, especially in their naïve form, demonstrate potent immunomodulatory effects by reducing pro-inflammatory cytokines and altering T cell dynamics in HS. Compared to adalimumab, MSCs offer a broader immunoregulatory profile, suggesting their potential as a multitarget therapy for HS. These findings support further clinical investigation of MSC-based treatments in managing this complex disease.