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

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.

A subset of IL-17+ mesenchymal stem cells possesses anti-Candida albicans effect

“…mostly immunosuppressive ones [12]. Furthermore, NO and IDO were reported to act as a switch in determining MSC-based immunosuppression or enhancing immune response [14]. The accumulated evidence suggests that MSCs may possess variable immunoregulatory function, but the detailed mechanism is unknown.…”

p53 regulates mesenchymal stem cell-mediated tumor suppression in a tumor microenvironment through immune modulation

“…64 Our previous studies also showed that tumor-resident MSCs are involved in orchestrating tumor microenvironment effects through recruitment of monocytes/ macrophages, thereby facilitate tumor growth. 29,30 Therefore, the effect of p53-deficient MSCs on tumor-resident macrophages also must be further investigated before we can complete the whole picture of the role of the tumor microenvironment in tumor growth.…”

“…MSCs from iNOS-deficient mice are ineffective in generating immunosuppression. 29,30 To determine whether p53 affects iNOS induction in MSCs, we stimulated wild-type or p53 À / À MSCs with interferon g (IFNg) and tumor necrosis factor a (TNFa; 10 ng/ml each). p53 À / À MSCs showed a striking increase in iNOS, in terms of mRNA and protein (Figures 4a and b), much higher than that occurred with p53 þ / þ or p53 þ / À MSCs.…”

“…We have shown that mouse MSCs can potently suppress immune responses through the concerted action of chemokines and nitric oxide (NO). 29,30 NO, derived from L-arginine through the enzymatic activity of inducible NO synthase (iNOS), has been reported to affect various inter-and intracellular signaling pathways, including induction of T-cell apoptosis 31 and inhibition of T-cell proliferation and cytokine production. 32 Furthermore, MSCs have the potential to affect the function and migration of other immune cells, including macrophages, dendritic cells and B cells.…”

Adult mesenchymal stem cells and the NO pathways

“…Data recently published (16) indicate that chemokines secreted by inflammatory cytokine-stimulated murine MSCs are responsible for the immune enhancement effects of MSCs and that immune function is regulated by iNOS. In this context, the relationship between SNO signaling as controlled by GSNOR and IDO has not been explored.…”