Mesenchymal Stem/Stromal Cells: Hyperinflammation and Immune Cell Dysregulation in C7 Hypomorphic Mouse Model of Recessive Dystrophic Epidermolysis Bullosa: Immune and Inflammation Modulation by Human Cord Blood Derived Unrestricted Somatic Stem Cells

Author Type(s)

Faculty

Document Type

Abstract

Publication Date

2022

DOI

10.1016/S1465-3249(22)00186-4

Journal Title

Cytotherapy

Department

Pediatrics

Abstract

Background & Aim: Background: Recessive dystrophic epidermolysis bullosa (RDEB) is secondary to mutations in col7a1 gene encoding type VII collagen (C7) and is manifested by persistent dermal blistering and inflammation, impaired wound healing and mutilating deformities. We previously demonstrated that human cord blood derived unrestricted somatic stem cells (USSCs) secret C7 and suppress TGFb fibrotic signaling in col7a1-/- mice (Liao/Cairo et al. 2018). The early demise, however, has limited investigations on the mechanisms of disease progression in this animal model. Objective: To utilize a C7hypo mouse model that express about 10% of wild type C7 and recapitulates human RDEB manifestations to investigate the mechanisms of inflammation and disease progression and to determine the effects of USSCs on modulating immune responses, suppressing fibrosis and progression of wound healing. Methods, Results & Conclusion: Results: We demonstrated immune dysregulation in C7hypo mice, based on a significant increase in neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte ratios, decrease in the lymphocyte- to-monocyte ratio, and significant elevation of IL-6 in the peripheral blood (p < 0.05). We further demonstrated significant increase on the levels of IL-6, IFN-γ, TNFα and IL- 17A in C7hypo paw skin lysate (p < 0.05), and the correlation between the severity of phenotypic manifestation and the levels of IL-6 and TNFα. This study also highlighted inflammation associated fibrosis in a subset of C7hypo mice: their paws were severely inflamed and transitioned into mitten deformity within a week instead of a gradual progression. Importantly, administration of USSCs significantly suppressed the development of mitten deformity in these mice (p < 0.05) and significantly decreased the NLR as compared to untreated control (0.77 ± 0.57 vs 2.52 ± 0.58; p < 0.05). Immunocytochemical analysis demonstrated that the paw skin of USSC treated C7hypo mice not only had a significantly higher relative ratio of CD4:CD8 T cells, but also an increased number of FoxP3+ Tregs than untreated control (p < 0.05). Furthermore, USSC administration promoted alternative polarization of macrophages, as demonstrated by increased expression of an anti- inflammatory M2 markers, CD206. Administration of USSCs also significantly facilitated wound healing in C7hypo mice. Conclusion: The results suggest RDEB is a systemic hyperinflammatory disorder and demonstrated the anti- inflammatory and anti-fibrotic functions of USSCs in the treatment of RDEB.

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