Adipose-Derived Stem Cells Ameliorate Allergic Airway Inflammation by Inducing Regulatory T Cells in a Mouse Model of Asthma

Abstract

Although several studies have demonstrated that mesenchymal stem cells derived from adipose tissue (ASCs) can ameliorate allergic airway inflammation, the immunomodulatory mechanism of ASCs remains unclear. In this study, we investigated whether regulatory T cells (Tregs) induction is a potential mechanism in immunomodulatory effects of ASCs on allergic airway disease and how these induced Tregs orchestrate allergic inflammation. Intravenous administration of ASCs significantly reduced allergic symptoms and inhibited eosinophilic inflammation. Airway hyperresponsiveness, total immune cell and eosinophils in the bronchoalveolar lavage fluid, mucus production, and serum allergen-specific IgE and IgG1 were significantly reduced after ASCs administration. ASCs significantly inhibited Th2 cytokines (IL-4, IL-5, and IL-13) and enhanced Th1 cytokine (IFN-γ) and regulatory cytokines (IL-10 and TGF-β) in the bronchoalveolar lavage fluid and lung draining lymph nodes. Furthermore, levels of IDO, TGF-β, and PGE2 were significantly increased after ASCs administration. Interestingly, this upregulation was accompanied by increased Treg populations. In conclusion, ASCs ameliorated allergic airway inflammation and improved lung function through the induction of Treg expansion. The induction of Treg by ASCs involves the secretion of soluble factors such as IDO, TGF-β, and PGE2 and Treg might be involved in the downregulation of Th2 cytokines and upregulation of Th1 cytokines production.

New Role of Adult Lung c-kit+Cells in a Mouse Model of Airway Hyperresponsiveness

“…IDO modulates the immune response by inducing a rapid depletion of the amino acid tryptophan and by leading to the formation of proapoptotic metabolites [37], whereas TGF β is able to downregulate the allergic response [56]. Moreover, IDO, TGF β , and prostaglandin E2 secreted by adipose-derived MSCs ameliorate airway inflammation and improve lung function [57]. The observations that GFP-labeled c-kit + cells were present within inflammatory infiltrates and that the apoptosis of inflammatory cells was higher in cell-treated animals support the hypothesis of local immunoregulation as a possible regulatory mechanism.…”

Biological effects and mechanisms of action of mesenchymal stem cell therapy in chronic obstructive pulmonary disease

“…13 Recent advances in mesenchymal stem cell (MSC) therapy have made this approach a strong candidate for clinical use in the treatment of several pulmonary diseases. [14][15][16][17] These multipotent nonhaematopoietic progenitors can be readily harvested from numerous tissues and expanded with high efficiency, and have strong immunosuppressive properties that can be exploited for successful autologous as well as heterologous transplantations. 18 Transplantation of MSCs has been reported in emphysemic rats, 14 murine asthma, 15 pulmonary hypertension in rats, 16 and acute lung injury in rats.…”

Indoleamine 2,3-Dioxygenase Is Not a Pivotal Regulator Responsible for Suppressing Allergic Airway Inflammation through Adipose-Derived Stem Cells

“…Although the immunomodulatory mechanism of MSCs in allergic airway diseases is not completely understood, the induction and expansion of Tregs may play an important role in the suppression of allergic airway inflammation by MSCs [12–15]. The expansion of Tregs by MSCs involves not only direct contact between MSCs and CD4 + T-cells, but also the induction of several mediators, such as PGE2, TGF-β, and IDO [30].…”

“…A mouse model of allergic airway inflammation was induced as previously reported with minor modifications [12,26]. Briefly, mice were sensitized by intraperitoneal injection of 75 μg ovalbumin (OVA, Sigma, St. Louis, MO; http://www.sigmaaldrich.com) with 2 mg aluminum hydroxide (Sigma) in 200 μL PBS on days 0, 1, 7, and 8.…”

“…Several studies have shown that mesenchymal stem cells (MSCs) provide a significant reduction in allergic airway inflammation and improve lung function [5–11]. Although the immunomodulatory mechanism of MSCs in allergic airway diseases remains to be elucidated, it has been suggested that upregulation of Tregs and increases in several soluble factors, such as prostaglandin E2 (PGE2), transforming growth factor-β (TGF-β), and interleukin (IL)-10 play critical roles in alleviating allergic airway inflammation through MSCs [12–15]. Furthermore, MSCs derived from adipose tissue (ASCs) significantly increase serum levels of PGE2 and the expression of TGF-β and indoleamine 2, 3-dioxygenase (IDO) in lung tissue responsible for the increase in Tregs in asthmatic mice [12].…”