Mesenchymal stem cells: a double-edged sword in regulating immune responses

Cell Death Differ. 2012 Sep;19(9):1505-13. doi: 10.1038/cdd.2012.26. Epub 2012 Mar 16.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation*
  • Chemokines / genetics
  • Chemokines / immunology
  • Humans
  • Hypersensitivity, Delayed / genetics
  • Hypersensitivity, Delayed / immunology
  • Immune Tolerance*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / immunology
  • Mesenchymal Stem Cells / immunology*
  • Mesenchymal Stem Cells / pathology
  • Mice
  • Mice, Knockout
  • Nitric Oxide / genetics
  • Nitric Oxide / immunology
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / immunology
  • Receptors, CCR5 / genetics
  • Receptors, CCR5 / immunology
  • Receptors, CXCR3 / genetics
  • Receptors, CXCR3 / immunology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology


  • Chemokines
  • Cxcr3 protein, mouse
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Receptors, CCR5
  • Receptors, CXCR3
  • Nitric Oxide
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse