Human Placental Mesenchymal Stem Cells (pMSCs) Play a Role as Immune Suppressive Cells by Shifting Macrophage Differentiation from Inflammatory M1 to Anti-inflammatory M2 Macrophages
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Mesenchymal stem cells (MSCs) have a therapeutic potential in tissue repair because of capacity for multipotent differentiation and their ability to modulate the immune response. In this study, we examined the ability of human placental MSCs (pMSCs) to modify the differentiation of human monocytes into macrophages and assessed the influence of pMSCs on important macrophage functions.
We used GM-CSF to stimulate the differentiation of monocytes into the M1 macrophage pathway and then co-cultured these cells with pMSCs in the early stages of macrophage differentiation. We then evaluated the effect on differentiation by microscopic examination and by quantification of molecules important in the differentiation and immune functions of macrophages using flow cytometry and ELISA. The mechanism by which pMSCs could mediate their effects on macrophage differentiation was also studied.
The co-culture of pMSCs with monocytes stimulated to follow the inflammatory M1 macrophage differentiation pathway resulted in a shift to anti-inflammatory M2-like macrophage differentiation. This transition was characterized by morphological of changes typical of M2 macrophages, and by changes in cell surface marker expression including CD14, CD36, CD163, CD204, CD206, B7-H4 and CD11b, which are distinctive of M2 macrophages. Co-culture with pMSCs reduced the expression of the costimulatory molecules (CD40, CD80 and CD86) and increased the expression of co-inhibitory molecules (CD273, CD274 and B7-H4) as well as the surface expression of major histocompatibility complex (MHC-II) molecules. Furthermore, the secretion of IL-10 was increased while the secretion of IL-1β, IL-12 (p70) and MIP-1α was decreased; a profile typical of M2 macrophages. Finally, pMSCs induced the phagocytic activity and the phagocytosis of apoptotic cells associated with M2- like macrophages; again a profile typical of M2 macrophages. We found that the immunoregulatory effect of pMSCs on macrophage differentiation was mediated by soluble molecules acting partially via glucocorticoid and progesterone receptors.
We have shown that pMSCs can transition macrophages from an inflammatory M1 into an anti-inflammatory M2 phenotype. Our findings suggest a new immunosuppressive property of pMSCs that may be employed in the resolution of inflammation associated with inflammatory diseases and in tissue repair.
KeywordsPlacenta mesenchymal stem cells Immune suppression Macrophages Inflammation
We would also like to thank the staff and patients of the Delivery Unit, King Abdul Aziz Medical City for their help in obtaining placentae. This study was supported by grants from King Abdulla International Medical Research Centre (Grant No. RC08/114) and King Abdulaziz City for Science and Technology (Grant No. ARP-29-186). Bill Kalionis was supported by NHMRC Grant No. 509178.
Conflict of Interest
The authors declare no potential conflicts of interest
- 3.Al Jumah, M. A., & Abumaree, M. H. (2012). The immunomodulatory and neuroprotective effects of mesenchymal stem cells (MSCs) in experimental autoimmune encephalomyelitis (EAE): a model of multiple sclerosis (MS). International Journal of Molecular Sciences, 13, 9298–9331.PubMedCrossRefGoogle Scholar
- 4.Abumaree, M., Al Jumah, M., Pace, R.A., Kalionis, B. (2011). Immunosuppressive properties of mesenchymal stem cells. Stem Cell Reviews.Google Scholar
- 10.Gupta, N., Su, X., Popov, B., Lee, J. W., Serikov, V., & Matthay, M. A. (2007). Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. Journal of Immunology, 179, 1855–1863.Google Scholar
- 13.Palucka, K. A., Taquet, N., Sanchez-Chapuis, F., & Gluckman, J. C. (1998). Dendritic cells as the terminal stage of monocyte differentiation. Journal of Immunology, 160, 4587–4595.Google Scholar
- 20.Chernykh, E. R., Shevela, E. Y., Sakhno, L. V., Tikhonova, M. A., Petrovsky, Y. L., Ostanin, A. A. (2010). The generation and properties of human M2-like macrophages: potential candidates for CNS repair? Cellular Therapy and Transplantation, 2.Google Scholar
- 21.Kigerl, K. A., Gensel, J. C., Ankeny, D. P., Alexander, J. K., Donnelly, D. J., & Popovich, P. G. (2009). Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience, 29, 13435–13444.CrossRefGoogle Scholar
- 29.Heng, B. C., Ye, C. P., Liu, H., et al. (2006). Loss of viability during freeze-thaw of intact and adherent human embryonic stem cells with conventional slow-cooling protocols is predominantly due to apoptosis rather than cellular necrosis. Journal of Biomedical Science, 13, 433–445.PubMedCrossRefGoogle Scholar
- 30.Verreck, F. A., de Boer, T., Langenberg, D. M., van der Zanden, L., & Ottenhoff, T. H. (2006). Phenotypic and functional profiling of human proinflammatory type-1 and anti-inflammatory type-2 macrophages in response to microbial antigens and IFN-gamma- and CD40L-mediated costimulation. Journal of Leukocyte Biology, 79, 285–293.PubMedCrossRefGoogle Scholar
- 40.Sallusto, F., & Lanzavecchia, A. (1994). Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. The Journal of Experimental Medicine, 179, 1109–1118.PubMedCrossRefGoogle Scholar
- 45.Ozkaynak, E., Wang, L., Goodearl, A., et al. (2002). Programmed death-1 targeting can promote allograft survival. Journal of Immunology, 169, 6546–6553.Google Scholar
- 54.Platt, N., Suzuki, H., Kurihara, Y., Kodama, T., & Gordon, S. (1996). Role for the class A macrophage scavenger receptor in the phagocytosis of apoptotic thymocytes in vitro. Proceedings of the National Academy of Sciences of the United States of America, 93, 12456–12460.PubMedCrossRefGoogle Scholar
- 58.Philippidis, P., Mason, J. C., Evans, B. J., et al. (2004). Hemoglobin scavenger receptor CD163 mediates interleukin-10 release and heme oxygenase-1 synthesis: antiinflammatory monocyte-macrophage responses in vitro, in resolving skin blisters in vivo, and after cardiopulmonary bypass surgery. Circulation Research, 94, 119–126.PubMedCrossRefGoogle Scholar