Mesenchymal stem cells (MSCs) are now known to display not only

Mesenchymal stem cells (MSCs) are now known to display not only adult stem cell multipotency but also strong anti-inflammatory and regenerative properties. remain at increased risk for premature death [1], particularly among young adults [2]. Up to 45% of cases present early end organ damage, related to prolonged activity or kidney disease [3]. Renal involvement, buy 761437-28-9 which occurs in 40 to 50% of patients in most series, is usually associated with mortality rates approximately eight occasions higher than expected [2], and remains only partially responsive to the best available treatments. Indeed, therapy with cyclophosphamide has not improved patient survival compared with corticosteroids [4], and the largest controlled trial comparing mycophenolate mofetil with intravenous cyclophosphamide in lupus nephritis achieved complete remission in only 8.6% and 8.1% of patients, respectively [5]. Undoubtedly there is usually a need for safer and more effective treatments for SLE. Mesenchymal stem cells Mesenchymal stromal cells, originally described in the 1960s as bone forming cells in the bone marrow [6], are now called multipotent mesenchymal stromal cells, or more commonly mesenchymal stem cells (MSCs) since they display adult stem cell multipotency. Thus, they differentiate into bone, cartilage and other connective tissues [7]. Unlike hematopoietic stem cells, which originate from bone marrow, MSCs can also buy 761437-28-9 be isolated from a variety of other tissues, such as umbilical cord or adipose tissue, and can be extensively expanded in vitro by up to 50 cell doublings without differentiation [8]. While these properties initially put MSCs center stage of an alleged era of regenerative medicine, the unexpected findings of Bartholomew and colleagues in 2002 [9] pointed to new features of these progenitor cells, the consequences of which are still being revealed in several areas of medicine. MSCs were found to escape T-cell recognition, suppress T-cell response to mitogens and also to prolong skin graft survival in baboons. In spite of a wide array of immunomodulatory effects that were subsequently confirmed to affect T and W lymphocytes, natural killer and antigen-presenting cells [10,11], MSCs remain hypoimmunogenic since they express low levels of major histocompatibility (MHC) class I molecules and do not express MHC class II or co-stimulatory (CD40, CD40L, CD80 or CD86) molecules [12]. Since the effects on immunocompetent cells are not MHC restricted, allogenic MSCs are widely used with no need to match them with host human leukocyte antigens (HLAs). The mechanisms underlying these effects are a subject of great scientific interest, as reviewed elsewhere in this issue, but apparently involve both cell contact and soluble factors, including indoleamine 2,3-dioxygenase, prostaglandin At the2, nitric oxide, transforming growth factor (TGF)- 1, IL-10, soluble HLA-G, and IL-1 receptor antagonists [13,14]. Also, several growth factors, such as hepatocyte growth factor, vascular endothelial growth factor (VEGF), insulin-like growth factor, epidermal growth factor, basic fibroblast buy 761437-28-9 growth factor and stromal cell-derived factor-1, among others, have been implicated in the modulatory and reparative effects of MSCs [15]. Recently, several studies have identified crucial functions for microRNAs (miRNAs) involved in proliferation, migration and differentiation of MSCs, suggesting that they might play an important role in the purchase of reparative MSC phenotypes [16]. Therapeutic use of MSCs in autoimmune and inflammatory diseases Given their vast proliferative potential, extensive immunosuppressive Mouse monoclonal to CD8.COV8 reacts with the 32 kDa a chain of CD8. This molecule is expressed on the T suppressor/cytotoxic cell population (which comprises about 1/3 of the peripheral blood T lymphocytes total population) and with most of thymocytes, as well as a subset of NK cells. CD8 expresses as either a heterodimer with the CD8b chain (CD8ab) or as a homodimer (CD8aa or CD8bb). CD8 acts as a co-receptor with MHC Class I restricted TCRs in antigen recognition. CD8 function is important for positive selection of MHC Class I restricted CD8+ T cells during T cell development properties, and also the ease of access to proper tissue sources, therapies with autologous or allogenic MSCs have been tested in a variety of immune-mediated disease models, including experimental allergic encephalomyelitis [17,18] – a model of multiple sclerosis – diabetic NOD/SCID mice [19], collagen-induced arthritis [20,21], and several lupus murine models [22-28]. Results have been mainly encouraging, but not altogether consistent, particularly in the case of arthritis [29], and lupus mice [26,27]. At the time of writing this review, 141 registered human trials on MSCs were found at the National Institutes of Health website [30], including 13 for graft versus host disease (GVHD), 10 for diabetes, 7 for Crohn’s disease or ulcerative colitis, 5 for multiple sclerosis, 2 for amyotrophic lateral sclerosis, one each for Sj?gren syndrome and systemic sclerosis and two for SLE. Some of these trials point to non-immune-mediated conditions that are associated with tissue injury, such as hepatic cirrhosis, myocardial infarction or congestive heart failure. In several instances it has become apparent that MSCs are not necessarily replacing diseased tissues or differentiating into individual cell lineages, but seem to exert a complex pattern of trophic, regenerative and anti-inflammatory effects [31,32]. In humans, the most studied application for MSCs is usually GVHD, a complication of hematopoietic stem cell transplantation in which donor T cells attack an immunocompromised and genetically disparate recipient [33]. In 2004, Le Blanc and colleagues [34] treated a.

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