Human Dermal Fibroblast-derived Spheroids Demonstrate Efficacious Immune Modulation in a Psoriasis Mouse Model

Abstract

BackgroundPsoriasis is a chronic inflammatory disease associated with high morbidity and few cases of sustained remission. Innovative immunomodulatory therapies, including fibroblast-based cell therapies, offer promising alternatives. This study investigates the therapeutic potential of human dermal fibroblasts (HDFs) organized into three-dimensional (3D) spheroids in a mouse model of imiquimod (IMQ)-induced psoriasis. MethodsHDF spheroids were cultured using Elplasia(R) microcavity plates, and their size, viability, and phenotype were compared with single cells in 2D monolayer cultures. Cellular responses in whole blood and acute inflammatory responses were evaluated at various time points following intravenous injection of HDFs. The therapeutic efficacy of HDF spheroids was assessed using an IMQ-induced psoriasis mouse model, with disease severity scored using the Psoriasis Area and Severity Index (PASI). Optimized HDF spheroids ([~]150 {micro}m, 1x106 cells/mouse) were administered intravenously in a single dose for mild psoriasis or multiple doses for moderate-to-severe psoriasis. The efficacy of HDF spheroids was compared to a pre-clinical monoclonal antibody targeting interleukin 23 (anti-IL-23). ResultsSpheroid cultures of HDFs showed reduced cell size, enhanced viability, and distinct phenotypic changes compared to monolayer cultures. Intravenous injection of HDF spheroids resulted in less thrombocytopenia and reduced acute inflammatory responses compared to single-cell injection. A single dose of HDF spheroids reduced the severity of mild psoriasis by 35%, while repeated doses resulted in a 36% reduction in moderate-to-severe psoriasis. Single-dose administration normalized blood cell counts, alleviated spleen enlargement, and improved cytokine dysregulation. Although HDF spheroids and anti-IL-23 reduced epidermal thickening and immune cell infiltration, HDF spheroids uniquely inhibited monocyte production and infiltration, a benefit not observed with anti-IL-23. No acute or chronic toxicity was observed. ConclusionsHDF spheroids offer comparable therapeutic efficacy to anti-IL-23 in treating psoriasis, with a distinct mechanism involving inhibiting monocyte production and infiltration. Their safety profile and broader immunomodulatory potential support their development as a novel therapeutic strategy for psoriasis and other inflammatory diseases.