Mesenchymal stromal cells (MSCs) are multipotent cells found in connective tissues that can differentiate into bone, cartilage, and adipose tissue. Interestingly, they can regulate immune responses in a paracrine way and allogeneic MSCs do not elicit immune response. These properties have encouraged a number of clinical trials in a broad range of regenerative therapies. Although these trials were first focused on their differentiation properties, in the last years, the immunosuppressive features have gained most of the attention. In this review, we will summarize the up-to-date knowledge about the immunosuppressive mechanisms of MSCs in vivo and in vitro and the most promising approaches in clinical investigation. 1. Introduction Mesenchymal stromal cells (MSCs) are found in a variety of tissues, although bone marrow represents the most common source for research and clinical purposes. These cells are multipotent progenitors that have the capacity to differentiate into multiple lineages such as bone, cartilage, and adipocytes [1–3]. MSCs have received renewed interest in the last five years, particularly due to their ability to modulate the immune response. This property, in combination with the facts that they are not immunogenic and preferentially home to damaged tissue, makes them good candidates for a therapeutic approach of cell-based therapy for a wide range of autoimmune disorders [4–6]. Currently, there are a large number of ongoing clinical trials employing MSCs as immunomodulators. MSCs have been shown to regulate the activity in a range of effector cells involved in both innate and adaptive immunities. The crosstalk between MSCs and the cells of the immune system leads to an increased production of several soluble immunomodulatory factors. Despite identification of many of these factors, the mechanism behind MSCs immunomodulation is not fully understood. However, the inflammatory environment and in particular the immune cells involved in each phase of the immune response are likely to be the critical determinants of the regulatory process. The immunosuppressive ability of MSCs is not constitutive but rather is induced by crosstalk with cells of the immune system [7–10]. Therefore, different inflammation status might lead to distinct immunomodulatory responses. This is a fundamental concept that could determine future clinical settings: treatment dose, timing, and frequency of administration, as well as the choice of the source of MSCs. 2. MSC-Mediated In Vitro Immunosuppression The ability of MSCs to modulate several processes of the immune
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