Modulation of Inflammation By Unrestricted Somatic Stem Cells (USSCs) to Suppress Fibrosis in Mice with Dystrophic Epidermolysis Bullosa

Background Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited dermal blistering disorder secondary to mutations in Col7a1 gene encoding type VII collagen (C7). Patients with RDEB suffer from life-long dermal blistering, impaired wound healing, mutilating fibrosis, and transformation into cutaneous squamous cell carcinoma. Our previous studies demonstrated that human cord blood derived unrestricted somatic stem cells (USSCs) express C7 and suppress TGFβ signaling in a col7a1−/− mouse model of RDEB. However, due to their early demise, identification of the mechanisms responsible for progressive fibrosis is not feasible in this animal model. Goal To investigate the role of inflammation in RDEB associated fibrosis and to determine the effects and mechanisms of USSC on modulating immune responses, suppressing fibrosis using a C7 hypomorphic (C7hypo) mouse model of RDEB that recapitulates the fibrotic disease progression seen in patients with RDEB. Results we demonstrated a correlation between hyperinflammation and fibrosis in a subgroup of RDEB mice with severe inflammation in their paws, which rapidly progressed to debilitating mutilations within one week, prior to excessive activation of transforming growth factor β signaling. Remarkably, systemic administration of cord blood derived unrestricted somatic stem cells (USSC) mitigated severe inflammation and digit mutilation in these mice. This therapeutic effect was achieved through the induction of anti-inflammatory macrophages and a restoration of imbalanced CD4:CD8 ratios. Similar immunomodulatory effects of USSCs were also observed in RDEB mice with a more gradual progression of fibrosis. Furthermore, USSCs significantly increased ratios of IL-1Ra to IL-1α in RDEB mouse skin, likely attributed to leukemia inhibitory factor (LIF) production by USSCs and subsequent endogenous upregulation of Suppressor of cytokine signaling 3 (SOCS3), a negative regulator of JAK/STAT and NFκB signaling pathways (Fig 1). Conclusions The results demonstrated that immune dysregulation resulting in hyperinflammation was among the early events facilitating fibrosis and persisted throughout disease progression in RDEB. The immunomodulatory effects of USSCs demonstrated in this study support the future clinical investigation of USSC in patients with RDEB.