Trained murine mesenchymal stem cells have anti‐inflammatory effect on macrophages, but defective regulation on T‐cell proliferation

Abstract

Mesenchymal stem cell (MSC)‐mediated immunomodulation affects both innate and adaptive immune systems. These responses to environmental cues, such as pathogen‐associated molecular patterns, damage‐associated molecular patterns, or proinflammatory cytokines, are crucial for resolution of inflammation, as well as successful tissue healing and regeneration. We observed that intermittent, repeated exposure of MSCs to LPS induced stronger NF‐κB activation than singular stimulation. A similar phenomenon, named innate immune memory or trained immunity, has been reported with macrophages. However, the potential regulation of “immune memory” in nonclassic immune cells, such as MSCs, has not been reported. In the current study, we chose IFN‐γ plus TNF‐α restimulation‐induced iNOS expression as a model of MSC activation, because IFN‐γ and TNF‐α play crucial roles in MSC‐mediated immunomodulation. The iNOS expression was enhanced in LPS‐trained MSCs, 3 d after a washout period following primary stimulation. LPS‐trained MSCs enhanced the anti‐inflammatory (arginase 1 and CD206) marker expression, but decreased the proinflammatory marker (TNF‐α, IL‐lβ, iNOS, and IL‐6) expression using an MSC‐macrophage coculture model. In contrast, LPS‐trained MSCs demonstrated a defective regulation on CD4 T‐cell proliferation. Mechanistic studies suggested that histone methylation and the JNK pathway are involved in LPS‐trained immunomodulation in MSCs. Our results demonstrate differential immunomodulatory effects of trained MSCs on macrophages and T cells. These immunomodulatory consequences are critical, because they will have a major impact on current MSC‐based cell therapies.—Lin, T., Pajarinen, J., Kohno, Y., Huang, J.‐F., Maruyama, M., Romero‐Lopez, M., Nathan, K., Yao, Z., Goodman, S. B. Trained murine mesenchymal stem cells have anti‐inflammatory effect on macrophages, but defective regulation on T‐cell proliferation. FASEB J. 33,4203–4211 (2019). http://www.fasebj.org

Genetically Modified Mouse Mesenchymal Stem Cells Expressing Non-Structural Proteins of Hepatitis C Virus Induce Effective Immune Response

“…Several authors have noted an increase in the antigen-presenting properties of MSCs as a result of IFN-γ pretreatment [72]. Other studies have shown that the "priming" of MSCs in vitro with IFN-γ, TNF-α, or IL-1β leads to the formation of the immunosuppressive phenotype MSC-2 [47,73,74]. Our results showed, for the first time, that after administration in mice, modified MSCs treated with IFN-γ cause a pronounced (tenfold) decrease in the cellular response.…”

Periprosthetic Osteolysis: Mechanisms, Prevention and Treatment

“…We have developed a pre-conditioning protocol for MSCs using short-term exposure of MSCs to TNFα and lipopolysaccharide (LPS) to enhance immunomodulation (by promoting polarization to an anti-inflammatory macrophage phenotype) and osteogenesis [178]. In addition, training MSCs by exposure to inflammatory cytokines and other substances appears to impart an innate immune memory of the prior stimulus [179]. We have also developed NF-κB sensing and IL-4 over-expressing genetically modified MSCs to treat chronic inflammation [176,180].…”

The microbiome and immune memory formation

“…Finally, stromal cells, which include fibroblasts and endothelial cells, also show memory to previous stimuli (reviewed in Reference ). Coculture of macrophages with LPS‐trained bone marrow‐derived mesenchymal stem cells in vitro led to reduced proinflammatory and enhanced anti‐inflammatory responses in the macrophages, which was associated with epigenetic alterations in the mesenchymal stem cells mesenchymal stem cells . The longevity of this effect was not determined but considering that mesenchymal stem cells are distributed in the perivascular niche of most tissues, microbial‐induced memory in these cells could be instrumental in defining immune responses.…”