title: Mesenchymal Stem Cells Induce Suppressive Macrophages Through Phagocytosis in a Mouse Model of Asthma.
abstract: 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. Stem Cells 2016;34:1836-1845.
authors.affiliation: INSERM, UMR1087, l'institut du thorax, Nantes, F-44000, France.|CNRS, UMR 6291, Nantes, F-44000, France.|Université de Nantes, Nantes, F-44000, France.
authors.forename: Faouzi
authors.initials: F
authors.lastname: Braza
authors.affiliation: INSERM, UMR1087, l'institut du thorax, Nantes, F-44000, France.|CNRS, UMR 6291, Nantes, F-44000, France.|Université de Nantes, Nantes, F-44000, France.|CHU de Nantes, Nantes, F-44000, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Dirou
authors.affiliation: INSERM, UMR1087, l'institut du thorax, Nantes, F-44000, France.|CNRS, UMR 6291, Nantes, F-44000, France.|Université de Nantes, Nantes, F-44000, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Forest
authors.affiliation: INSERM, UMR1087, l'institut du thorax, Nantes, F-44000, France.|CNRS, UMR 6291, Nantes, F-44000, France.|Université de Nantes, Nantes, F-44000, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Sauzeau
authors.affiliation: INSERM, UMR1087, l'institut du thorax, Nantes, F-44000, France.|CNRS, UMR 6291, Nantes, F-44000, France.|Université de Nantes, Nantes, F-44000, France.
authors.forename: Dorian
authors.initials: D
authors.lastname: Hassoun
authors.affiliation: INSERM, UMR1087, l'institut du thorax, Nantes, F-44000, France.|CNRS, UMR 6291, Nantes, F-44000, France.|Université de Nantes, Nantes, F-44000, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Chesné
authors.affiliation: INSERM, UMR1087, l'institut du thorax, Nantes, F-44000, France.|CNRS, UMR 6291, Nantes, F-44000, France.|Université de Nantes, Nantes, F-44000, France.
authors.forename: Marie-Aude
authors.initials: MA
authors.lastname: Cheminant-Muller
authors.affiliation: INSERM, UMR1087, l'institut du thorax, Nantes, F-44000, France.|CNRS, UMR 6291, Nantes, F-44000, France.|Université de Nantes, Nantes, F-44000, France.|CHU de Nantes, Nantes, F-44000, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Sagan
authors.affiliation: INSERM, UMR1087, l'institut du thorax, Nantes, F-44000, France.|CNRS, UMR 6291, Nantes, F-44000, France.|Université de Nantes, Nantes, F-44000, France.|CHU de Nantes, Nantes, F-44000, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Magnan
authors.affiliation: INSERM, UMR1087, l'institut du thorax, Nantes, F-44000, France.|CNRS, UMR 6291, Nantes, F-44000, France.|Université de Nantes, Nantes, F-44000, France.|CHU de Nantes, Nantes, F-44000, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Lemarchand
mesh_terms: D000818:Animals; D001249:Asthma / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D016084:Bronchoconstriction; D016764:Cell Polarity; D004195:Disease Models, Animal; D006967:Hypersensitivity / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D007249:Inflammation / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D007275:Injections, Intravenous; D008168:Lung / Q000473:pathology; D008264:Macrophages / Q000378:metabolism*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D010587:Phagocytosis; D010641:Phenotype; D039981:Pyroglyphidae / Q000502:physiology; D012130:Respiratory Hypersensitivity / Q000150:complications / Q000473:pathology / Q000503:physiopathology
keywords: Airway hyper-responsiveness; Airway smooth muscle contraction; House dust mite asthma; M2 macrophage; Mesenchymal stem cells; Phagocytosis