Human Bone Marrow Stromal Cells Lose Immunosuppressive and Anti-inflammatory Properties upon Oncogenic Transformation

Multipotent mesenchymal stromal cells (MSCs) have generated considerable interest in the fields of regenerative medicine, cell therapy and immune modulation. Over the past 5 years, the initial observations that MSCs could enhance regeneration and modulate immune responses have been significantly advanced and we now have a clearer picture of the effects that MSCs have on the immune system particularly in the context of inflammatory-mediated disorders. A number of mechanisms of action have been reported in MSC immunomodulation, which encompass the secretion of soluble factors, induction of anergy, apoptosis, regulatory T cells and tolerogenic dendritic cells. It is clear that MSCs modulate both innate and adaptive responses and evidence is now emerging that the local microenvironment is key in the activation or licensing of MSCs to become immunosuppressive. More recently, studies have suggested that MSCs have the capacity to sense their environment and have a role in pathogen clearance in conjunction with the resolution of insult or injury. This review focuses on the mechanisms of MSC immunomodulation discussing the multistep process of MSC localisation at sites of inflammation, the cross talk between MSCs and the local microenvironment as well as the subsequent mechanisms of action used to resolve inflammation.

In the past decade, the therapeutic value of mesenchymal stromal cells (MSCs) has been studied in various indications, thereby taking advantage of their immunosuppressive properties. Easy procurement from bone marrow, adipose tissue or other sources and conventional in vitro expansion culture have made their clinical use attractive. Bridging the gap between current scientific knowledge and regulatory prospects on the transformation potential and possible tumorigenicity of MSCs, the Cell Products Working Party and the Committee for Advanced Therapies organized a meeting with leading European experts in the field of MSCs. This meeting elucidated the risk of potential tumorigenicity related to MSC-based therapies from two angles: the scientific perspective and the regulatory point of view. The conclusions of this meeting, including the current regulatory thinking on quality, nonclinical and clinical aspects for MSCs, are presented in this review, leading to a clearer way forward for the development of such products. Copyright © 2013 International Society for Cellular Therapy. All rights reserved.

Adult mesenchymal stem cells were recently found to suppress effector T cell and inflammatory responses and have emerged as attractive therapeutic candidates for immune disorders. In rheumatoid arthritis (RA), a loss in the immunological self-tolerance causes the activation of autoreactive T cells against joint components and subsequent chronic inflammation. The aim of this study is to characterise the immunosuppressive activity of human adipose-derived mesenchymal stem cells (hASCs) on collagen-reactive T cells from patients with RA. The effects of hASCs on collagen-reactive RA human T cell proliferation and cytokine production were investigated, as well as effects on the production of inflammatory mediators by monocytes and fibroblast-like synoviocytes from patients with RA. hASCs suppressed the antigen-specific response of T cells from patients with RA. hASCs inhibited the proliferative response and the production of inflammatory cytokines by collagen-activated CD4 and CD8 T cells. In contrast, the numbers of IL10-producing T cells and monocytes were significantly augmented upon hASC treatment. The suppressive activity of hASCs was cell-to-cell contact dependent and independent. hASCs also stimulated the generation of FoxP3 protein-expressing CD4(+)CD25(+) regulatory T cells, with the capacity to suppress collagen-specific T cell responses. Finally, hASCs downregulated the inflammatory response and the production of matrix-degrading enzymes by synovial cells isolated from patients with RA. The present work identifies hASCs as key regulators of immune tolerance, with the capacity to suppress T cell and inflammatory responses and to induce the generation/activation of antigen-specific regulatory T cells.