title: 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-γ, TNF-α, IL-6, MCP-1, nitric oxide (NO) and PGE2 production and facilitated CD4(+) /CD8(+) T cell, CD11b(high) 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-κB activation in M. abscessus-infected macrophages cultured in the presence of IFN-γ. Inhibiting NO or NF-κB signaling using specific inhibitors reduced the antimycobacterial activity of MSCs. Furthermore, the cellular crosstalk between TNF-α released from IFN-γ-stimulated M. abscessus-infected macrophages and PGE2 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.
authors.affiliation: Department of Microbiology and Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Jong-Seok
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Animal Stem Cells Research Lab, Animal and Plant Quarantine Agency, Anyang-si, Gyeonggi-do, South Korea.
authors.forename: Sang-Ho
authors.initials: SH
authors.lastname: Cha
authors.affiliation: Department of Microbiology and Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Woo Sik
authors.initials: WS
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Seung Jung
authors.initials: SJ
authors.lastname: Han
authors.affiliation: Department of Microbiology and Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Seung Bin
authors.initials: SB
authors.lastname: Cha
authors.affiliation: Department of Microbiology and Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Hong Min
authors.initials: HM
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Kee Woong
authors.initials: KW
authors.lastname: Kwon
authors.affiliation: Department of Microbiology and Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: So Jeong
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Choi
authors.affiliation: Animal Stem Cells Research Lab, Animal and Plant Quarantine Agency, Anyang-si, Gyeonggi-do, South Korea.
authors.forename: Jienny
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Microbiology and Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Sang-Nae
authors.initials: SN
authors.lastname: Cho
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Won-Jung
authors.initials: WJ
authors.lastname: Koh
authors.affiliation: Department of Immunology, Lab of Dendritic Cell Differentiation & Regulation, School of Medicine, Konkuk University, Chungju, South Korea.
authors.forename: Yeong-Min
authors.initials: YM
authors.lastname: Park
authors.affiliation: Department of Microbiology and Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Sung Jae
authors.initials: SJ
authors.lastname: Shin
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D015232:Dinoprostone / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009165:Mycobacterium Infections, Nontuberculous / Q000382:microbiology* / Q000473:pathology / Q000628:therapy*; D000073358:Mycobacterium abscessus / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016207:Cytokines; D006146:Guanidines; D016328:NF-kappa B; D009569:Nitric Oxide; D015232:Dinoprostone; C004479:pimagedine
keywords: Cell interactions; Cellular therapy; Cytokines; Mesenchymal stem cells; Stem cell-microenvironment interactions