Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase

Abstract

Human multipotent mesenchymal stromal cells (MSCs) exhibit multilineage differentiation potential, support hematopoiesis, and inhibit proliferation and effector function of various immune cells. On the basis of these properties, MSC are currently under clinical investigation in a range of therapeutic applications including tissue repair and immune-mediated disorders such as graft-versus-host-disease refractory to pharmacological immunosuppression. Although initial clinical results appear promising, there are significant concerns that application of MSC might inadvertently suppress antimicrobial immunity with an increased risk of infection. We demonstrate here that on stimulation with inflammatory cytokines human MSC exhibit broad-spectrum antimicrobial effector function directed against a range of clinically relevant bacteria, protozoal parasites and viruses. Moreover, we identify the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) as the underlying molecular mechanism. We furthermore delineate significant differences between human and murine MSC in that murine MSC fail to express IDO and inhibit bacterial growth. Conversely, only murine but not human MSC express inducible nitric oxide synthase on cytokine stimulation thus challenging the validity of murine in vivo models for the preclinical evaluation of human MSC. Collectively, our data identify human MSC as a cellular immunosuppressant that concurrently exhibits potent antimicrobial effector function thus encouraging their further evaluation in clinical trials.

Guanylate-binding protein 1 (GBP1) contributes to the immunity of human mesenchymal stromal cells against Toxoplasma gondii

“…In mice, MSCs rely on nitric oxide (NO) produced by iNOS to protect themselves (9). Interestingly, we found that the expression of iNOS (NOS2) and human IRG genes was close to zero in MSCs both before and after stimulation with IFN-γ, which was also the case for the constitutive NOS (NOS1 and NOS3) genes, further supporting the notion that iNOS shows no increase in expression after stimulation.…”

“…2D, siRNAmediated IDO knockdown also could not rescue the parasite from IFN-γ-mediated growth inhibition. These results suggest that the ability of human MSCs inhibiting the growth of T. gondii does not depend on Trp deprivation or IDO activity, which is in contrast to the results presented from a previously reported study (9).…”

“…The antimicrobial effect of unstimulated hMSCs is mediated by the cathelicidin, LL-37 (4), as shown both in vitro and in vivo. In IFN-γ-stimulated hMSCs, by contrast, the antibacterial effect is mediated through the tryptophan-catabolizing enzyme, indoleamine 2,3-dioxygenase (IDO) (9). Conflicting results are also reported in mouse, in which the decision as to whether mMSCs increase the activity of phagocytes or not depends on the origin of these cells (11).…”

“…Data from murine colitis models have shown that human adipose-derived MSCs protect against dextran-induced colitis by decreasing the secretion of proinflammatory cytokines and chemokines (6). However, the antimicrobial effector molecules in vertebrate MSCs are not universally the same (4)(5)(6)(7)(8)(9)(10)(11). The antimicrobial effect of unstimulated hMSCs is mediated by the cathelicidin, LL-37 (4), as shown both in vitro and in vivo.…”

14S,21R-dihydroxy-docosahexaenoic Acid Treatment Enhances Mesenchymal Stem Cell Amelioration of Renal Ischemia/Reperfusion Injury

“…For example, hMSCs, but not mMSCs, possess antimicrobial properties against a range of clinically relevant bacteria through their ability to up-regulate the expression of indoleamine 2,3-dioxygenase [68]. Additionally, mMSCs, but not hMSCs, express inducible nitric oxide synthase [68], and it has been shown that hMSCs and mMSCs express different mMSC lysates were analyzed by western blot. P-Akt quantities relative to Akt were measured based on optical densities of the gel bands, and normalized to that of hypoxia control (n = 4).…”