Mesenchymal Stem Cells: A Double-edged Sword in Regulating Immune Responses

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Departmental Papers (Dental)
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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
Dentistry
Oral and Maxillofacial Surgery
Oral Biology and Oral Pathology
Periodontics and Periodontology
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Li, Wenzhao
Ren, Guangwen
Huang, Yan
Su, Juanjuan
Han, Yanyan
Li, Jiao
Chen, Xiaodong
Cao, Kai
Chen, Qing
Shou, Peishun
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Abstract

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.

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2012-09-01
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Cell Death and Differentiation
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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.
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