Abstract
The objective of this study was to investigate the effect of human adipose tissue-derived mesenchymal stem cells (AdMSCs) on atopic dermatitis (AD) in the BALB/c mouse model. The AdMSCs attenuated clinical symptoms associated with AD, decreased numbers of degranulated mast cells (MCs), IgE level, amount of histamine released, and prostaglandin E2 level. Atopic dermatitis increased the expression levels of cytokines/chemokines, such as interleukin-5 (IL-5), macrophage inflammatory protein-1ß (MIP-1ß), MIP-2, chemokine (C-C motif) ligand 5 (CCL5), and IL-17, in BALB/c mouse. The AdMSCs showed decreased expression levels of these cytokines in the mouse model of AD. In vivo downregulation of MIP-2 attenuated the clinical symptoms associated with AD. Atopic dermatitis increased the expression levels of hallmarks of allergic inflammation, induced interactions of Fc𝜀RIβ with histone deacetylase 3 (HDAC3) and Lyn, increased ß-hexosaminidase activity, increased serum IgE level, and increased the amount of histamine released in an MIP-2-dependent manner. Downregulation of MIP-2 increased the levels of several miRNAs, including miR-122a-5p. Mouse miR-122a-5p mimic inhibited AD, while suppressor of cytokine signaling 1 (SOCS1), a predicted downstream target of miR-122a-5p, was required for AD. The downregulation of SOCS1 decreased the expression levels of MIP-2 and chemokine (C-X-C motif) ligand 13 (CXCL13) in the mouse model of AD. The downregulation of CXCL13 attenuated AD and allergic inflammation such as passive cutaneous anaphylaxis. The role of T cell transcription factors in AD was also investigated. Atopic dermatitis increased the expression levels of T-bet and GATA-3 [transcription factors of T-helper 1 (Th1) and T-helper 2 (Th2) cells, respectively] but decreased the expression of Foxp3, a transcription factor of regulatory T (Treg) cells, in an SOCS1-dependent manner. In addition to this, miR-122a-5p mimic also prevented AD from regulating the expression of T-bet, GATA-3, and Foxp3. Atopic dermatitis increased the expression of cluster of differentiation 163 (CD163), a marker of M2 macrophages, but decreased the expression of inducible nitric oxide synthase (iNOS), a marker of M1 macrophages. Additionally, SOCS1 and miR-122a-5p mimic regulated the expression of CD163 and iNOS in the mouse model of AD. Experiments employing conditioned medium showed interactions between MCs and macrophages in AD. The conditioned medium of AdMSCs, but not the conditioned medium of human dermal fibroblasts, negatively inhibited the features of allergic inflammation. In summary, we investigated the anti-atopic effects of AdMSCs, identified targets of AdMSCs, and determined the underlying mechanism for the anti-atopic effects of AdMSCs.
Highlights
Mesenchymal stem cells (MSCs) are multipotent stem cells that can be isolated from various tissues, including bone marrow, umbilical cord and adipose tissue
Staining with hematoxylin & eosin (H&E) showed that epidermal hyperplasia and lymphocyte infiltration induced by atopic dermatitis (AD) were attenuated by Adipose tissue-derived mesenchymal stem cells (AdMSCs), but not by human dermal fibroblast (HDF) (Figure 2A)
Toluidine blue staining showed that AdMSCs, but not HDFs, decreased the number of degranulated mast cells (MCs) in the mouse model of AD (Figures 2B,C)
Summary
Mesenchymal stem cells (MSCs) are multipotent stem cells that can be isolated from various tissues, including bone marrow, umbilical cord and adipose tissue. They interact with both innate and adaptive immune systems, resulting in a suppressive effect on the activation of immune cells, including T cells, B cells, dendritic cells, and natural killer (NK) cells (Asari et al, 2009; Prigione et al, 2009). Mesenchymal stem cells can ameliorate allergic diseases such as asthma, rhinitis, and dermatitis (Nemeth et al, 2010; Kavanagh and Mahon, 2011; Kapoor et al, 2012), and MSCs suppress chronic asthmatic changes in male rats (Ahmadi et al, 2016). The overexpression of C-X-C motif chemokine receptor 5 (CXCR5) is known to intensify the immunomodulatory effects of MSCs, and it decreases allergic contact dermatitis (ACD) (Zhang et al, 2017)
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