Pretreatment with interferon-γ enhances the therapeutic activity of mesenchymal stromal cells in animal models of colitis.
TL;DR: It is demonstrated that IFN‐γ activation of MSCs increases their immunosuppresive capacities and importantly, their therapeutic efficacy in vivo, and prestimulation of MMSs with IFN-γ enhances their capacity to inhibit Th1 inflammatory responses, resulting in diminished mucosal damage in experimental colitis.
Abstract: Mesenchymal stromal cells (MSCs) are currently under investigation for the treatment of inflammatory disorders, including Crohn's disease. MSCs are pluripotent cells with immunosuppressive properties. Recent data suggest that resting MSCs do not have significant immunomodulatory activity, but that the immunosuppressive function of MSCs has to be elicited by interferon-γ (IFN-γ). In this article, we assessed the effects of IFN-γ prestimulation of MSCs (IMSCs) on their immunosuppressive properties in vitro and in vivo. To this end, we pretreated MSCs with IFN-γ and assessed their therapeutic effects in dextran sodium sulfate (DSS)- and trinitrobenzene sulfonate (TNBS)-induced colitis in mice. We found that mice treated with IMSCs (but not MSCs) showed a significantly attenuated development of DSS-induced colitis. Furthermore, IMSCs alleviated symptoms of TNBS-induced colitis. IMSC-treated mice displayed an increase in body weight, lower colitis scores, and better survival rates compared with untreated mice. In addition, serum amyloid A protein levels and local proinflammatory cytokine levels in colonic tissues were significantly suppressed after administration of IMSC. We also observed that IMSCs showed greater migration potential than unstimulated MSCs to sites within the inflamed intestine. In conclusion, we show that prestimulation of MSCs with IFN-γ enhances their capacity to inhibit Th1 inflammatory responses, resulting in diminished mucosal damage in experimental colitis. These data demonstrate that IFN-γ activation of MSCs increases their immunosuppresive capacities and importantly, their therapeutic efficacy in vivo.
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TL;DR: Current insights into the ways in which MSCs sense and control inflammation are outlined, highlighting the central role of macrophage polarization and progress toward clinical application is discussed.
1,086 citations
Cites background from "Pretreatment with interferon-γ enha..."
...Other studies have indicated that pretreatment with inflammatory cytokines can amplify the therapeutic effect of MSCs in animal models of colitis and acute myocardial ischemia/reperfusion injury (Duijvestein et al., 2011; Luo et al., 2012)....
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...The polarization of T cells toward a Treg phenotype has been also shown in other experimental models of autoimmune and inflammatory diseases, such as SLE, diabetes, and colitis (Choi et al., 2012; Madec et al., 2009; Duijvestein et al., 2011)....
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TL;DR: The current findings on the immunoregulatory plasticity of MSCs in disease pathogenesis and therapy are reviewed.
Abstract: Mesenchymal stem cells (MSCs) are multipotent stromal cells that exist in many tissues and are capable of differentiating into several different cell types. Exogenously administered MSCs migrate to damaged tissue sites, where they participate in tissue repair. Their communication with the inflammatory microenvironment is an essential part of this process. In recent years, much has been learned about the cellular and molecular mechanisms of the interaction between MSCs and various participants in inflammation. Depending on their type and intensity, inflammatory stimuli confer on MSCs the ability to suppress the immune response in some cases or to enhance it in others. Here we review the current findings on the immunoregulatory plasticity of MSCs in disease pathogenesis and therapy.
1,035 citations
TL;DR: Current understanding of the immunomodulatory mechanisms of MSCs and issues related to their therapeutic application are discussed, which suggest the plasticity of immunoregulation by M SCs is controlled by the intensity and complexity of inflammatory stimuli.
Abstract: Mesenchymal stem cells (MSCs; also referred to as mesenchymal stromal cells) have attracted much attention for their ability to regulate inflammatory processes. Their therapeutic potential is currently being investigated in various degenerative and inflammatory disorders such as Crohn’s disease, graft-versus-host disease, diabetic nephropathy and organ fibrosis. The mechanisms by which MSCs exert their therapeutic effects are multifaceted, but in general, these cells are thought to enable damaged tissues to form a balanced inflammatory and regenerative microenvironment in the presence of vigorous inflammation. Studies over the past few years have demonstrated that when exposed to an inflammatory environment, MSCs can orchestrate local and systemic innate and adaptive immune responses through the release of various mediators, including immunosuppressive molecules, growth factors, exosomes, chemokines, complement components and various metabolites. Interestingly, even nonviable MSCs can exert beneficial effects, with apoptotic MSCs showing immunosuppressive functions in vivo. Because the immunomodulatory capabilities of MSCs are not constitutive but rather are licensed by inflammatory cytokines, the net outcomes of MSC activation might vary depending on the levels and the types of inflammation within the residing tissues. Here, we review current understanding of the immunomodulatory mechanisms of MSCs and the issues related to their therapeutic applications.
628 citations
TL;DR: This review focuses on the crosstalk between MSCs and immune responses and their potential clinical applications, especially in inflammatory diseases.
Abstract: Mesenchymal stem cells (MSCs) can be isolated from almost all tissues and effectively expanded in vitro. Although their true in situ properties and biological functions remain to be elucidated, these in vitro expanded cells have been shown to possess potential to differentiate into specific cell lineages. It is speculated that MSCs in situ have important roles in tissue cellular homeostasis by replacing dead or dysfunctional cells. Recent studies have demonstrated that in vitro expanded MSCs of various origins have great capacity to modulate immune responses and change the progression of different inflammatory diseases. As tissue injuries are often accompanied by inflammation, inflammatory factors may provide cues to mobilize MSCs to tissue sites with damage. Before carrying out tissue repair functions, MSCs first prepare the microenvironment by modulating inflammatory processes and releasing various growth factors in response to the inflammation status. In this review, we focus on the crosstalk between MSCs and immune responses and their potential clinical applications, especially in inflammatory diseases.
617 citations
TL;DR: A synthesis of the current status of mesenchymal stem cells is provided, which shows that there are bidirectional interactions between MSCs and inflammatory cells, which determine the outcome of MSC-mediated tissue repair processes.
519 citations
References
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TL;DR: The Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy proposes minimal criteria to define human MSC, believing this minimal set of standard criteria will foster a more uniform characterization of MSC and facilitate the exchange of data among investigators.
14,724 citations
TL;DR: It is postulate that mesenchymal stem cells have a potent immunosuppressive effect in vivo and are transplanted in a patient with severe treatment-resistant grade IV acute graft-versus-host disease of the gut and liver.
2,636 citations
TL;DR: The results suggest that the distribution of MSCs throughout the post-natal organism is related to their existence in a perivascular niche, which has implications for understanding MSC biology, and for clinical and pharmacological purposes.
Abstract: Mesenchymal stem cells (MSCs) are multipotent cells which can give rise to mesenchymal and non-mesenchymal tissues in vitro and in vivo. Whereas in vitro properties such as (trans)differentiation capabilities are well known, there is little information regarding natural distribution and biology in the living organism. To investigate the subject further, we generated long-term cultures of cells with mesenchymal stem cell characteristics from different organs and tissues from adult mice. These populations have morphology, immunophenotype and growth properties similar to bone marrow-derived MSCs. The differentiation potential was related to the tissue of origin. The results indicate that (1) cells with mesenchymal stem characteristics can be derived and propagated in vitro from different organs and tissues (brain, spleen, liver, kidney, lung, bone marrow, muscle, thymus, pancreas); (2) MSC long-term cultures can be generated from large blood vessels such as the aorta artery and the vena cava, as well as from small vessels such as those from kidney glomeruli; (3) MSCs are not detected in peripheral blood. Taken together, these results suggest that the distribution of MSCs throughout the post-natal organism is related to their existence in a perivascular niche. These findings have implications for understanding MSC biology, and for clinical and pharmacological purposes.
2,340 citations
TL;DR: Baboon MSCs have been observed to alter lymphocyte reactivity to allogeneic target cells and tissues, which may prove useful in future applications of tissue regeneration and stem cell engineering.
2,273 citations
TL;DR: It is found that proinflammatory cytokines are required to induce immunosuppression by MSCs through the concerted action of chemokines and NO.
1,789 citations