Mesenchymal Stem Cells Induce Suppressive Macrophages Through Phagocytosis in a Mouse Model of Asthma

A bstract Mesenchymal stem cell (MSC) immunosuppressive functions make them attractive candidates for anti‐inflammatory therapy in allergic asthma. However, the mechanisms by which they ensure therapeutic effects remain to be elucidated. In an acute mouse model of house dust mite (Der f)‐induced asthma, one i.v. MSC injection was sufficient to normalize and stabilize lung function in Der f‐sensitized mice as compared to control mice. MSC injection decreased in vivo airway responsiveness and decreased ex vivo carbachol‐induced bronchial contraction, maintaining bronchial expression of the inhibitory type 2 muscarinic receptor. To evaluate in vivo MSC survival, MSCs were labeled with PKH26 fluorescent marker prior to i.v. injection, and 1 to 10 days later total lungs were digested to obtain single‐cell suspensions. 91.5 ± 2.3% and 86.6 ± 6.3% of the recovered PKH26 + lung cells expressed specific macrophage markers in control and Der f mice, respectively, suggesting that macrophages had phagocyted in vivo the injected MSCs. Interestingly, only PKH26 + macrophages expressed M2 phenotype, while the innate PKH26 − macrophages expressed M1 phenotype. Finally, the remaining 0.5% PKH26 + MSCs expressed 10‐ to 100‐fold more COX‐2 than before injection, suggesting in vivo MSC phenotype modification. Together, the results of this study indicate that MSCs attenuate asthma by being phagocyted by lung macrophages, which in turn acquire a M2 suppressive phenotype. S tem C ells 2016;34:1836–1845