Immunosuppression by mesenchymal stem cells: mechanisms and clinical applications

Mesenchymal stem cells (MSCs), also named multipotent mesenchymal stromal cells, are largely studied as new therapeutic tools for a number of clinical applications. Indeed, these cells have been shown to have differentiation capacities as well as paracrine effects via the secretion of growth factors, cytokines, antifibrotic or angiogenic mediators [1]. A large body of studies also indicates that MSCs possess an immunosuppressive function both in vitro and in vivo. We review the present knowledge on the mechanisms underlying the immunomodulatory characteristics of MSCs and their applications in animal models of immune suppression or in clinics.MSCs were initially isolated from bone marrow but are now shown to reside in almost every type of connective tissue [2]. MSCs are characterized as a heterogeneous population of cells that proliferate in vitro as plastic-adherent cells able to develop as fibroblast colony forming-units [3]. MSCs are distinguished from hematopoietic cells by being negative for the cell surface markers CD11b, CD14, CD34, CD45 and human leukocyte antigen (HLA)-DR but expressing CD73, CD90 and CD105. Importantly, the capacity to differentiate into multiple mesenchymal lineages including bone, fat and cartilage is used as a functional criterion to define MSCs [4].MSC-mediated immunosuppression requires preliminary activation of the MSCs by immune cells through the secretion of the proinflammatory cytokine IFNγ, alone or together with TNFα, IL-1α or IL-1β [5,6]. This activation step has also been shown in vivo in a model of graft versus host disease (GVHD) since recipients of IFNγ-/- T cells did not respond to MSC treatment and succumbed to GVHD [7]. Indeed, MSCs from mice deficient for the IFNγ receptor 1 do not have immunosuppressive activity, highlighting the important role of IFNγ in this process [6].Although target cell-MSC interactions may play a role, the MSC-mediated immunosuppression mainly acts through the secretion of soluble molecules that