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      Mesenchymal stem cells reciprocally regulate the M1/M2 balance in mouse bone marrow-derived macrophages

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          Abstract

          Mesenchymal stem cells (MSCs) have been widely studied for their applications in stem cell-based regeneration. During myocardial infarction (MI), infiltrated macrophages have pivotal roles in inflammation, angiogenesis and cardiac remodeling. We hypothesized that MSCs may modulate the immunologic environment to accelerate regeneration. This study was designed to assess the functional relationship between the macrophage phenotype and MSCs. MSCs isolated from bone marrow and bone marrow-derived macrophages (BMDMs) underwent differentiation induced by macrophage colony-stimulating factor. To determine the macrophage phenotype, classical M1 markers and alternative M2 markers were analyzed with or without co-culturing with MSCs in a transwell system. For animal studies, MI was induced by the ligation of the rat coronary artery. MSCs were injected within the infarct myocardium, and we analyzed the phenotype of the infiltrated macrophages by immunostaining. In the MSC-injected myocardium, the macrophages adjacent to the MSCs showed strong expression of arginase-1 (Arg1), an M2 marker. In BMDMs co-cultured with MSCs, the M1 markers such as interleukin-6 (IL-6), IL-1β, monocyte chemoattractant protein-1 and inducible nitric oxide synthase (iNOS) were significantly reduced. In contrast, the M2 markers such as IL-10, IL-4, CD206 and Arg1 were markedly increased by co-culturing with MSCs. Specifically, the ratio of iNOS to Arg1 in BMDMs was notably downregulated by co-culturing with MSCs. These results suggest that the preferential shift of the macrophage phenotype from M1 to M2 may be related to the immune-modulating characteristics of MSCs that contribute to cardiac repair.

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          Most cited references15

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          Macrophages in Tumor Microenvironments and the Progression of Tumors

          Macrophages are widely distributed innate immune cells that play indispensable roles in the innate and adaptive immune response to pathogens and in-tissue homeostasis. Macrophages can be activated by a variety of stimuli and polarized to functionally different phenotypes. Two distinct subsets of macrophages have been proposed, including classically activated (M1) and alternatively activated (M2) macrophages. M1 macrophages express a series of proinflammatory cytokines, chemokines, and effector molecules, such as IL-12, IL-23, TNF- α , iNOS and MHCI/II. In contrast, M2 macrophages express a wide array of anti-inflammatory molecules, such as IL-10, TGF- β , and arginase1. In most tumors, the infiltrated macrophages are considered to be of the M2 phenotype, which provides an immunosuppressive microenvironment for tumor growth. Furthermore, tumor-associated macrophages secrete many cytokines, chemokines, and proteases, which promote tumor angiogenesis, growth, metastasis, and immunosuppression. Recently, it was also found that tumor-associated macrophages interact with cancer stem cells. This interaction leads to tumorigenesis, metastasis, and drug resistance. So mediating macrophage to resist tumors is considered to be potential therapy.
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            Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages.

            Mesenchymal stem cells (MSCs) are capable of modulating the immune system through interaction with a wide range of immune cells. This study investigates the hypothesis that interaction of MSCs with macrophages could play a significant role in their antiinflammatory/immune modulatory effects. MSCs were derived from bone marrow and monocytes were isolated from peripheral blood of healthy donors. We cultured human monocytes for 7 days without any added cytokines to generate macrophages, and then cocultured them for 3 more days with culture-expanded MSCs. We used cell surface antigen expression and intracellular cytokine expression patterns to study the immunophenotype of macrophages at the end of this coculture period, and phagocytic assays to investigate their functional activity in vitro. Macrophages cocultured with MSCs consistently showed high-level expression of CD206, a marker of alternatively activated macrophages. Furthermore, these macrophages expressed high levels of interleukin (IL)-10 and low levels of IL-12, as determined by intracellular staining, typical of alternatively activated macrophages. However, macrophages cocultured with MSCs also expressed high levels of IL-6 and low levels of tumor necrosis factor-alpha (TNF-alpha) compared to controls. Functionally, macrophages cocultured with MSCs showed a higher level of phagocytic activity. We describe a novel type of human macrophage generated in vitro after coculture with MSCs that assumes an immunophenotype defined as IL-10-high, IL-12-low, IL-6-high, and TNF-alpha-low secreting cells. These MSC-educated macrophages may be a unique and novel type of alternatively activated macrophage with a potentially significant role in tissue repair.
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              Mouse Bone Marrow-Derived Mesenchymal Stromal Cells Turn Activated Macrophages into a Regulatory-Like Profile

              In recent years it has become clear that the therapeutic properties of bone marrow-derived mesenchymal stromal cells (MSC) are related not only to their ability to differentiate into different lineages but also to their capacity to suppress the immune response. We here studied the influence of MSC on macrophage function. Using mouse thioglycolate-elicited peritoneal macrophages (M) stimulated with LPS, we found that MSC markedly suppressed the production of the inflammatory cytokines TNF-α, IL-6, IL-12p70 and interferon-γ while increased the production of IL-10 and IL-12p40. Similar results were observed using supernatants from MSC suggesting that factor(s) constitutively released by MSC are involved. Supporting a role for PGE2 we observed that acetylsalicylic acid impaired the ability of MSC to inhibit the production of inflammatory cytokines and to stimulate the production of IL-10 by LPS-stimulated M. Moreover, we found that MSC constitutively produce PGE2 at levels able to inhibit the production of TNF-α and IL-6 by activated M. MSC also inhibited the up-regulation of CD86 and MHC class II in LPS-stimulated M impairing their ability to activate antigen-specific T CD4+ cells. On the other hand, they stimulated the uptake of apoptotic thymocytes by M. Of note, MSC turned M into cells highly susceptible to infection with the parasite Trypanosoma cruzi increasing more than 5-fold the rate of M infection. Using a model of inflammation triggered by s.c. implantation of glass cylinders, we found that MSC stimulated the recruitment of macrophages which showed a low expression of CD86 and the MHC class II molecule Iab and a high ability to produce IL-10 and IL-12p40, but not IL-12 p70. In summary, our results suggest that MSC switch M into a regulatory profile characterized by a low ability to produce inflammatory cytokines, a high ability to phagocyte apoptotic cells, and a marked increase in their susceptibility to infection by intracellular pathogens.
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                Author and article information

                Journal
                Exp Mol Med
                Exp. Mol. Med
                Experimental & Molecular Medicine
                Nature Publishing Group
                1226-3613
                2092-6413
                January 2014
                10 January 2014
                1 January 2014
                : 46
                : 1
                : e70
                Affiliations
                [1 ]Research Laboratory of Cardiovascular Regeneration, Chonnam National University Hospital , Gwangju, South Korea
                [2 ]Department of Cardiology, Chonnam National University Hospital , Gwangju, South Korea
                [3 ]Heart Research Center, Chonnam National University Hospital , Gwangju, South Korea
                [4 ]Department of Internal Medicine, School of Medicine, Chosun University , Gwangju, South Korea
                Author notes
                [* ]Heart Research Center, Chonnam National University Hospital , 8 Hak-dong, Dong-gu, Gwangju 501-757, Korea. E-mail: retissue@ 123456chonnam.ac.kr
                [* ]Department of Cardiology, Chonnam National University Hospital , 8 Hak-dong, Dong-gu, Gwangju 501-757, Korea. E-mail: cecilyk@ 123456chonnam.ac.kr
                Article
                emm2013135
                10.1038/emm.2013.135
                3909888
                24406319
                88ec5713-e68d-407a-b254-4b6f09ad4e4b
                Copyright © 2014 KSBMB.

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                History
                : 01 July 2013
                : 20 August 2013
                : 12 September 2013
                Categories
                Original Article

                Molecular medicine
                mesenchymal stem cell,macrophage,myocardial infarction,immunologic environment

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