Hyperinflammation And Immune Cell Dysregulation In A Hypomorphic Animal Model (C7hypo) Of Recessive Dystrophic Epidermolysis Bullosa (RDEB): Immunomodulation By Human Cord Blood Derived Unrestricted Somatic Stem Cells (USSCs)

Author Type(s)

Faculty

Document Type

Abstract

Publication Date

2022

DOI

10.1002/pbc.29735

Journal Title

Pediatric Blood and Cancer

Department

Pediatrics

Abstract

Background: RDEB is secondary to mutations in the Col7a1 gene encoding collagen VII (C7) and manifested by life-long dermal blistering, impaired wound healing, persistent inflammation, and mutilating deformities. Our previous studies demonstrated that human cord blood derived unrestricted somatic stem cells (USSCs) secret C7 and suppress TGFβ signaling induced fibrosis in RDEB (Liao/Cairo et al. 2018). Objective: To investigate the mechanisms of inflammation and to determine the immunomodulatory effects of USSCs, using a C7hypo mouse model of RDEB. Methods: 0.2 x 106 USSCs in 20μl PBS we are injected intra-hepatically in the newborn C7hypo mice. Complete blood count with differential was measured using hematology analyzer (Zoetis Diagnostics). Cytokines in the plasma and skin lysate were quantitated using BD CBA mouse Th1/Th2/Th17 cytokine kit. Results: The C7hypo mice exhibited biomarkers for systemic inflammation, including significantly higher neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte (PLR) ratios, lower lymphocyte-to-monocyte ratio (LMR), and elevated plasma IL-6, as compared to the wild type (WT) (p < 0.05). IL-6, IFN-γ, TNFα and IL-17A were also significantly elevated in the C7hypo paw skin lysate than theWT (p < 0.05).While the PLR and LMR were not significantly changed by USSC administration, the NLR was significantly decreased in the USSC treated C7hypo mice (0.77 ± 0.57) as compared to the untreated control (2.52 ± 0.58; p < 0.05) and was comparable to the WT (0.17 ± 0.02; p > 0.05). In the skin lysate of USSC-treated C7hypo mice, the levels of IL-6, IFN-γ, TNFα and IL-17A were still significantly higher than those in the WT (p < 0.05), however, the magnitude of elevation was decreased as compared to the untreated group. More importantly, the skin lysate from USSC-treated mice exhibited a trend of increasing IL-2 and IL-10, both of which have been implicated in the induction of regulatory T (Treg) cells. Immunocytochemical analysis further 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. Conclusions: These preliminary results suggest RDEB is a systemic hyperinflammatory disorder and highlight the immunomodulatory role of cord blood derived USSCs in the treatment for RDEB. This research was conducted at New York Medical College, Valhalla, NY, USA.

This document is currently not available here.

Share

COinS