A Novel Therapeutic Approach Using Mesenchymal Stem Cells to Protect Against Mycobacterium abscessus

Abstract

Recent studies have demonstrated the therapeutic potential of mesenchymal stem cells (MSCs) for the treatment of acute inflammatory injury and bacterial pneumonia, but their therapeutic applications in mycobacterial infections have not been investigated. In this study, we demonstrated the use of MSCs as a novel therapeutic strategy against Mycobacterium abscessus (M. abscessus), which is the most drug-resistant and difficult-to-treat mycobacterial pathogen. The systemic intravenous injection of MSCs not only improved mouse survival but also enhanced bacterial clearance in the lungs and spleen. Additionally, MSCs enhanced IFN-c, TNFa, IL-6, MCP-1, nitric oxide (NO) and PGE 2 production and facilitated CD4high macrophage, and monocyte recruitment in the lungs of M. abscessus-infected mice. To precisely elucidate the functions of MSCs in M. abscessus infection, an in vitro macrophage infection system was used. MSCs caused markedly increased NO production via NF-jB activation in M. abscessus-infected macrophages cultured in the presence of IFN-c. Inhibiting NO or NF-jB signaling using specific inhibitors reduced the antimycobacterial activity of MSCs. Furthermore, the cellular crosstalk between TNF-a released from IFN-c-stimulated M. abscessus-infected macrophages and PGE 2 produced by MSCs was necessary for the mycobacterial-killing activity of the macrophages. Finally, the importance of increased NO production in response to MSC administration was confirmed in the mouse M. abscessus infection model. Our results suggest that MSCs may offer a novel therapeutic strategy for treating this drug-resistant mycobacterial infection by enhancing the bacterial-killing power of macrophages. STEM CELLS 2016;34:1957-1970 SIGNIFICANCE STATEMENTMycobacterium abscessus is resistant to many antibiotics, thus making it difficult to obtain a successful treatment outcome. Here, we demonstrated that the administration of mesenchymal stem cell (MSCs) has significant potential in the treatment of M. abscessus infection. We found that the systemic injection of MSCs improved mouse survival and enhanced bacterial clearance in the lungs. In subsequent in vitro studies, we discovered that MSCs increased NO production in M. abscessus-infected macrophages through NF-jB activation in the presence of IFN-g. We further demonstrated that the cellular crosstalk between TNF-a and PGE 2 was essential for the increased NO production in macrophages.

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