Disease-specific primed human adult stem cells effectively ameliorate experimental atopic dermatitis in mice

Abstract

Although human mesenchymal stem cells (hMSCs) hold considerable promise as an alternative therapeutic reagent for allergic disorders including atopic dermatitis (AD), the strategy for enhancing hMSC-based therapy remains challenging. We sought to investigate whether preconditioning with mast cell (MC) granules could enhance the therapeutic efficiency of human umbilical cord blood-derived MSCs (hUCB-MSCs) against AD. Methods: AD was experimentally induced in NC/Nga mice by repeated applications of 4% sodium dodecyl sulfate (SDS) and dermatophagoides farinae (Df) extract, and preconditioned hUCB-MSCs were subcutaneously injected. The therapeutic effect was determined by gross examination and additional ex vivo experiments performed using blood and skin samples to determine the resolution of allergic inflammation. To explore the underlying mechanisms, several co-culture assays with primary isolated immune cells and wound closure assays were conducted. Results: Pretreatment of MC granules enhanced the therapeutic effects of hUCB-MSCs by attenuating the symptoms of AD in an experimental animal model. MC granule-primed cells suppressed the activation of major disease-inducing cells, MCs and B lymphocytes more efficiently than naïve cells both in vitro and in vivo . Histamine-mediated upregulation of the COX-2 signaling pathway was shown to play a crucial role in suppression of the allergic immune response by MC-pretreated hUCB-MSCs. Moreover, MC pretreatment improved the wound healing ability of hUCB-MSCs. Conclusions: Our findings indicate that pre-exposure to MC granules improved the therapeutic effect of hUCB-MSCs on experimental AD by resolving the allergic immune reaction and accelerating the tissue regeneration process more efficiently than naïve cells, suggesting a potential enhancement strategy for stem cell-based therapy.

Mesenchymal Stem Cells and Atopic Dermatitis: A Review

“…In BALB/c mice with AD induced by ovalbumin (OVA), treatment with superoxide dismutase 3-transduced MSCs (SOD3-MSCs) suppressed the recruitment of T cells into the skin and reduced the number of CD4 + and CD8 + T cells in the spleen and lymph node (Sah et al, 2018). A similar inhibitory effect on T cell recruitment to the skin was observed in BALB/c mice with AD induced by Aspergillus fumigatus (Af ) and treated with hUCB-MSCs primed with poly I:C or IFN-γ and in NC/Nga mice with AD induced by Df and treated with hUCB-MSCs pretreated with MC granules (Lee et al, 2019;Park et al, 2019).…”

“…In vitro experiments have confirmed the inhibitory effects of different types of MSCs on IgE production by B cells stimulated with lipopolysaccharide (LPS) or anti-CD40, as well as the inhibition of B cell proliferation and maturation (Na et al, 2014;Shin et al, 2017a;Lee et al, 2019). Interestingly, the effects of MSCs on B cell were attenuated with the addition of celecoxib, a selective COX-2 inhibitor (Shin et al, 2017b;Lee et al, 2019).…”

“…An intravenous injection of BM-MSCs was shown to suppress AD via inhibition of IgE production by B cells (Na et al, 2014). A reduction in IgE production in sera was also found in NC/Nga mice with AD induced by Df and treated with hAD-MSCs or hUCB-MSCs (Shin et al, 2017b;Lee et al, 2019).…”

“…Another example of the complexity of stem cell-based therapy was demonstrated in a study in which hUCB-MSCs were pretreated with MC granules, enhancing their therapeutic effects, as observed by the attenuation of AD signs in a NC/Nga mouse model. Moreover, it was shown that hUCB-MSCs primed with mast cell granules suppressed the activation of MCs and B lymphocytes more efficiently than naïve MSCs, both in vitro and in vivo (Lee et al, 2019).…”

Impact of Mesenchymal Stem Cell Senescence on Inflammaging

“…In contrast, an age-mediated increase in the production of DAMPs or alarmins can reportedly fuel the progression of inflammaging. MSC treatment has emerged as an anti-aging therapy because of its unique immunomodulatory function and tissue regenerative capacity (32,33). Especially, paracrine secretion of MSCs plays a crucial role in clinical feasibility, including anti-aging therapy, and with these secretory factors, the conditioned medium (CM) of MSCs can be administered to various diseases.…”