title: A local application of mesenchymal stem cells and cyclosporine A attenuates immune response by a switch in macrophage phenotype.
abstract: The immunosuppressive effects of systemically administered mesenchymal stem cells (MSCs) and immunosuppressive drugs have been well documented. We analysed the mechanisms underlying the therapeutic effect of MSCs applied locally in combination with non-specific immunosuppression in a mouse model of allogeneic skin transplantation. The MSC-seeded and cyclosporine A (CsA)-loaded nanofibre scaffolds were applied topically to skin allografts in a mouse model and the local immune response was assessed and characterized. MSCs migrated from the scaffold into the side of injury and were detected in the graft region and draining lymph nodes (DLNs). The numbers of graft-infiltrating macrophages and the production of nitric oxide (NO) were significantly decreased in recipients treated with MSCs and CsA, and this reduction correlated with impaired production of IFNγ in the graft and DLNs. In contrast, the proportion of alternatively activated macrophages (F4/80+CD206+cells) and the production of IL-10 by intragraft macrophages were significantly upregulated. The ability of MSCs to alter the phenotype of macrophages from the M1 type into an M2 population was confirmed in a co-culture system in vitro. We suggest that the topical application of MSCs in combination with CsA induces a switch in macrophages to a population with an alternatively activated 'healing' phenotype and producing elevated levels of IL-10. These alterations in macrophage phenotype and function could represent one of the mechanisms of immunosuppressive action of MSCs applied in combination with CsA. Copyright © 2015 John Wiley & Sons, Ltd.
authors.affiliation: Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Hajkova
authors.affiliation: Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic.|Department of Transplantation Immunology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Eliska
authors.initials: E
authors.lastname: Javorkova
authors.affiliation: Department of Transplantation Immunology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Alena
authors.initials: A
authors.lastname: Zajicova
authors.affiliation: Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic.|Department of Transplantation Immunology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Peter
authors.initials: P
authors.lastname: Trosan
authors.affiliation: Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic.|Department of Transplantation Immunology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Holan
authors.affiliation: Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic.|Department of Transplantation Immunology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Krulova
mesh_terms: D064591:Allografts; D000818:Animals; D002454:Cell Differentiation; D016572:Cyclosporine / Q000494:pharmacology*; D005260:Female; D006085:Graft Survival / Q000187:drug effects*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016038:Skin Transplantation
chemical_list: D016572:Cyclosporine
keywords: cyclosporine A; local immunosuppression; macrophages; mesenchymal stem cells; nanofibres