Mesenchymal stem cells and innate tolerance: biology and clinical applications

The properties of mesenchymal stem cells (MSC) have been widely investigated during the last decade, from their differentiation capacity to their immunosuppressive effect on any type of immune cell. These properties have been successfully harnessed for the treatment of inflammatory diseases such as graft versus host disease (GvHD). Different mechanisms have been proposed for their immunosuppressive properties, although it seems likely that they are used in concert. The inflammatory environment to which MSC are exposed plays a pivotal role in activating their functions. Conversely, the interplay of MSC with the immunoregulatory networks recruited during inflammation is fundamental to the delivery of immunosuppression. Since other types of terminally differentiated stromal cells share these properties, it is plausible that sternness is not a required feature. Therefore these functions may be involved in the physiological control of acute inflammation in various tissues. These notions highlight the importance of investigating the role of stromal cells as modulators of immune responses. Mesenchymal stem cells (MSC) are multipotent progenitor cells of stromal origin, originally isolated from adult bone marrow and subsequently from other tissues including in both adult and foetal life [1-9]. Even though MSC are defined according to their ability to differentiate into various tissues of mesodermal origin (osteocytes, chondrocytes, adipocytes), there are unconfirmed reports that they can also differentiate into endothelial cells [10], as well as neural cells [11], and cells of endodermal origin [12]. The identification of MSC with the use of specific markers remains elusive. They are commonly described as expressing CD73, CD105, CD90 and negative for the haematopoietic (CD45) and vascular (CD31) markers [13]. In mouse MSC markers of embryonic origin such as SSCA-1 [14] and SSCA-4 [15] have been identified, but more recently the co-expression of PDGFR alpha and Sca-1 [16] appears to be particularly effective at selectively identifying MSC because the vast majority of cells with progenitor activity resides in this subset. The efforts at detecting markers of human MSC have not delivered consistent results, but have indicated that they may preferentially express markers of neuronal lineage like low-affinity nerve growth factor receptor-1 (LNFGR1) [17] and ganglioside GD2 [18]. Although these markers have not been entirely confirmed, the notion of the neuroepithelial origin of MSC has recently been supported by an elegant study showing that Sox1(+) neuroepithelial cells supply the earliest wave of MSC differentiation during embryogenesis [19]. Pre-MSC type cells with characteristics of pluripotency have been isolated in the bone marrow or in foetal/perinatal tissues. Good examples are multipotent adult progenitor cells (MAPC), which differentiate into various lineages in vitro using defined cytokine combinations, and when transplanted they directly contribute to haematopoiesis in vivo and generate long-term repopulating haematopoietic stem cells and the full repertoire of haematopoietic progenitors [20]. The relative ease with which MSC can be isolated from adult tissues and the lack of ethical concern have probably been the main reason for their popularity. MSC have been successfully tested for their ability to protect from a variety of tissue injuries both in experimental [21-23] and clinical [24] settings.