Mesenchymal stem cells (MSCs) are strongly immunosuppressive in vivo and in vitro in both animals and humans. Using cloned MSCs from mouse bone marrow, we have shown that MSCs potently inhibit TCR-activated proliferation and cytokine production of freshly-isolated splenocytes. In vivo, MSCs prevented the rejection of allogeneic skin transplants, suppressed antigen-specific DTH responses, and inhibited graft-versus-host disease (GvHD) in mice. Interestingly, MSCs did not affect the IL-2-driven proliferation of T cell blasts, which do not produce inflammatory cytokines unless re-activated. The immunosuppressive effect of MSCs requires the co-presence of IFN3 and another cytokine - either TNF1, IL-11 or IL-12. Such cytokine pairs provoked MSCs to express inducible nitric oxide synthase (iNOS), produce NO, and secrete of large amounts of T cell specific-chemokines, which complement the activity of NO: in co-cultures, these chemokines drove T cells to migrate into proximity with MSCs, where high levels of NO can suppress T cells. Blockade of NO production or chemokine receptors reversed the inhibition of T cells. We recently found that while human MSCs are equally effective in suppressing T cells and have a similar spectrum of chemokine production, they utilize IDO to affect immunosuppression. Thus, we hypothesize that proinflammatory cytokines induce MSCs to produce chemokines and NO (in mouse) or IDO (in human) which act in concert to mediate immunosuppression. We propose two specific aims to prove this hypothesis using mouse and human MSCs to complement each other. We will first investigate the role of chemokines and NO or IDO in mediating immunosuppression of MSCs in both mouse cells and human cells in vitro and in the mouse GvHD model in vivo. Next, we will determine the molecular mechanisms of the regulation of IDO and NO in mouse and human MSC. Since MSC-mediated immunosuppression occurs through inflammatory cytokine-upregulation of iNOS/IDO and chemokines, a better understanding of the mechanisms underlying these effects will lead to better clinical protocols for immune disorders, cancer immunotherapy and vaccine design.
One of the most important properties of mesenchymal stem cells is their high potency in suppressing immune reactions, which can be involved in many diseases such autoimmune disorders, allergic reactions, rejection of transplants and graft-versus-host disease associated with bone marrow transplantation. It is likely that the very first clinical application of stem cell research will be the use of mesenchymal stem cells to treat immune disorders. Therefore, the proposed studies are expected to have enormous relevance to human health.
|Shou, P; Chen, Q; Jiang, J et al. (2016) Type I interferons exert anti-tumor effect via reversing immunosuppression mediated by mesenchymal stromal cells. Oncogene 35:5953-5962|
|Chen, Qing; Shou, Peishun; Zhang, Liying et al. (2014) An osteopontin-integrin interaction plays a critical role in directing adipogenesis and osteogenesis by mesenchymal stem cells. Stem Cells 32:327-37|
|Ren, G; Liu, Y; Zhao, X et al. (2014) Tumor resident mesenchymal stromal cells endow naïve stromal cells with tumor-promoting properties. Oncogene 33:4016-20|
|Ling, Weifang; Zhang, Jimin; Yuan, Zengrong et al. (2014) Mesenchymal stem cells use IDO to regulate immunity in tumor microenvironment. Cancer Res 74:1576-87|
|Zhang, J; Roberts, A I; Liu, C et al. (2013) A novel subset of helper T cells promotes immune responses by secreting GM-CSF. Cell Death Differ 20:1731-41|
|Shi, Yufang; Su, Juanjuan; Roberts, Arthur I et al. (2012) How mesenchymal stem cells interact with tissue immune responses. Trends Immunol 33:136-43|
|Ren, Guangwen; Zhao, Xin; Wang, Ying et al. (2012) CCR2-dependent recruitment of macrophages by tumor-educated mesenchymal stromal cells promotes tumor development and is mimicked by TNF?. Cell Stem Cell 11:812-24|
|Ren, Guangwen; Chen, Xiaodong; Dong, Fengping et al. (2012) Concise review: mesenchymal stem cells and translational medicine: emerging issues. Stem Cells Transl Med 1:51-8|
|Li, W; Ren, G; Huang, Y et al. (2012) Mesenchymal stem cells: a double-edged sword in regulating immune responses. Cell Death Differ 19:1505-13|
|Krause, Christopher D; Izotova, Lara S; Ren, Gwangwen et al. (2011) Efficient co-expression of bicistronic proteins in mesenchymal stem cells by development and optimization of a multifunctional plasmid. Stem Cell Res Ther 2:15|