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 6 2.3% and 86.6 6 6.3% of the recovered PKH26 1 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 1 macrophages expressed M2 phenotype, while the innate PKH26 2 macrophages expressed M1 phenotype. Finally, the remaining 0.5% PKH26 1 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.

The influence of macrophages on mesenchymal stromal cell therapy: passive or aggressive agents?

“…Interestingly, macrophages characterized as F4/80 + CD11c + which phagocytosed MSC expressed higher mRNA levels of TGF‐β and IL‐10 and lower mRNA levels of IL‐6 than cells that did not engulf MSC (Fig. ) .…”

“…An array of studies have demonstrated the capacity for MSC to modulate inflammatory M1 macrophages and promote anti‐inflammatory M2 macrophages . The recent progress made in the field of immunometabolism has been reflected in the MSC field, with Selleri et al .…”

Therapeutic administration of bone marrow‐derived mesenchymal stromal cells reduces airway inflammation without up‐regulating Tregs in experimental asthma

“…The immunomodulatory potential of non-hematopoietic multipotent precursor cells resident in connective tissue, namely mesenchymal stromal cells (MSCs), has encouraged studies of their application as an alternative to glucocorticoid therapy in asthma. [16][17][18] Nonetheless, prophylactic cell therapy in OVA models of asthma has some limitations. [11][12][13] The administration of MSCs has been performed before or immediately after sensitization with ovalbumin (OVA) in experimental asthma, hampering the Th2-biased immune response in a mechanism dependent on Treg cell expansion in the lung and in secondary lymphoid organs.…”

The effects of conditioned media generated by polarized macrophages on the cellular behaviours of bone marrow mesenchymal stem cells

“…In this study, Mφ polarization was induced by various cytokine stimuli , and conditioned media (CMs) derived from polarized Mφs (CM0, CM1 and CM2) was used to investigate the impact of Mφs on the properties of bone marrow mesenchymal stem cells (BMMSCs). It should be noted that stimulating factors were completely removed before the supernatants of polarized Mφs were collected for CM production . In addition, the application of CM in investigations can prevent changes in Mφ polarization when directly co‐cultured with BMMSCs, as there is evidence that MSCs exert significant effects on macrophages during in vitro culture .…”