Departmental Papers (Dental)
Date of this Version
Cell Death and Differentiation
Mesenchymal stem cells (MSCs) have been employed successfully to treat various immune disorders in animal models and clinical settings. Our previous studies have shown that MSCs can become highly immunosuppressive upon stimulation by inflammatory cytokines, an effect exerted through the concerted action of chemokines and nitric oxide (NO). Here, we show that MSCs can also enhance immune responses. This immune-promoting effect occurred when proinflammatory cytokines were inadequate to elicit sufficient NO production. When inducible nitric oxide synthase (iNOS) production was inhibited or genetically ablated, MSCs strongly enhance T-cell proliferation in vitro and the delayed-type hypersensitivity response in vivo. Furthermore, iNOS-/- MSCs significantly inhibited melanoma growth. It is likely that in the absence of NO, chemokines act to promote immune responses. Indeed, in CCR5-/- CXCR3-/- mice, the immune-promoting effect of iNOS-/- MSCs is greatly diminished. Thus, NO acts as a switch in MSC-mediated immunomodulation. More importantly, the dual effect on immune reactions was also observed in human MSCs, in which indoleamine 2,3-dioxygenase (IDO) acts as a switch. This study provides novel information about the pathophysiological roles of MSCs. © 2012 Macmillan Publishers Limited All rights reserved.
Author keywords: chemokine, immunomodulation, mesenchymal stem cells, tissue repair MeSH: Animals, Cell Proliferation, Chemokines, Humans, Hypersensitivity, Delayed, Immune Tolerance, Indoleamine-Pyrrole 2, 3, -Dioxygenase, Mesenchymal Stromal Cells, Mice, Mice, Knockout, Nitric Oxide, Nitric Oxide Synthase Type II, Receptors, CCR5, Receptors, CXCR3, T-Lymphocytes Species Index: Animalia, Mus EMTREE drug terms: chemokine receptor CCR5, chemokine receptor CXCR3, gamma interferon, indoleamine 2, 3 dioxygenase, inducible nitric oxide synthase, nitric oxide, tumor necrosis factor alpha EMTREE medical terms: animal experiment, animal model, article, cancer inhibition, controlled study, delayed hypersensitivity, immunomodulation, immunoregulation, in vitro study, lymphocyte proliferation, melanoma, mesenchymal stem cell, mouse, nonhuman, priority journal, T lymphocyte
Li, W., Ren, G., Huang, Y., Su, J., Han, Y., Li, J., Chen, X., Cao, K., Chen, Q., Shou, P., Zhang, L., Yuan, Z., Roberts, A. I., Shi, S., Le, A. D., & Shi, Y. (2012). Mesenchymal Stem Cells: A Double-edged Sword in Regulating Immune Responses. Cell Death and Differentiation, 19 (9), 1505-1513. http://dx.doi.org/10.1038/cdd.2012.26
Oral and Maxillofacial Surgery Commons, Oral Biology and Oral Pathology Commons, Periodontics and Periodontology Commons
Date Posted: 10 February 2023
This document has been peer reviewed.
At the time of publication, author Songtao Shi was affiliated with the University of Southern California School of Dentistry. Currently, (s)he is a faculty member at the School of Dental Medicine at the University of Pennsylvania.
At the time of publication, author Anh D. Le was affiliated with the University of Southern California School of Dentistry. Currently, (s)he is a faculty member at the School of Dental Medicine at the University of Pennsylvania.