These effects are mediated by prostaglandin E2(PGE2) and indoleamine 2,3-dioxygenase (IDO)[13,26]. == Determine 1. Immunomodulatory, Regulatory T cell, Angiogenesis, Vascular endothelial growth factor, Diabetes mellitus == INTRODUCTION == According to the International Diabetes Federation (IDF) database, the number of patients with diabetes mellitus (DM) worldwide is 285 million, indicating that 6.4% of the global population have DM. Furthermore, the IDF predict that the number will increase to 438 million by 2030. DM is a serious disease; approximately 4 million people die each year from DM. In addition, DM is a major cause of serious complications such as blindness, renal failure, and ischemic heart disease. Type 1 diabetes is characterized by the irreversible autoimmune destruction of pancreatic cells and is usually diagnosed in children and young adults[1]. Islet transplantation consists of the transplantation of pancreatic islets that have been isolated from a donor pancreas[2]. The therapeutic effect was regarded as insufficient for a long time; however, since the use of the Edmonton Protocol[2], a markedly improved islet transplant protocol developed at Alberta University, islet transplantation has been performed widely for 10 years. However, according to a recent report, although approximately 70% of patients did not need daily insulin one year after transplantation, approximately 90% of patients required insulin after five years[3]. Therefore, studies aimed at improving the outcome of islet transplantation are still required. One of the reasons for failure of insulin independence is islet graft loss due to a variety of causes including instant blood-mediated inflammatory reaction[4], acute rejection[5], islet toxicity by immunosuppressive brokers[6], and ischemia caused by poor vascularity at transplantation[7] and the embolization effect ER81 of the islets[8]. Moreover, islet transplantation also faces the problem of a limited supply of suitable donor human pancreata[9]. Thus, to promote islet transplantation in the future, there is a need to establish a novel donor source and develop more effective treatments to prolong the function of transplanted islets. == WHAT ARE MESENCHYMAL STEM CELLS? == Mesenchymal stem cells (MSCs) are multipotent cells capable of self-renewal and differentiation into a various cell lineages. They are derived from many organs such as bone marrow, adipose tissue, skin, fetal liver, and umbilical cord blood[10,11]. Although the number of MSCs in the bone marrow is very small compared with other component cells (only 0.01%-0.001%)[12], MSCs regulate the maintenance and proliferation of hematopoietic stem cells (HSCs) in the bone marrow[13]. MSCs are able to differentiate into various cells derived from ectoderm (epithelial cells and neurons), mesoderm (connective stroma, cartilage, fat and bone cells), and endoderm (muscle cells, gut epithelial cells, and lung cells)[13]. A number of groups have demonstrated that insulin-producing cells could also be differentiated from MSCs[14-18]. The regeneration of insulin-producing cells is an important theme in research aiming to improve the outcome of cell replacement therapy and has been the focus of some groups. However, in an alternative approach, many studies have examined the effect of transplanting islets with MSCs and have demonstrated improved islet function when co-transplanted with MSCs[7,19-22]. The beneficial effects of MSCs in the context of islet transplantation could be attributed to immunomodulation and angiogenesis. == IMMUNOMODULATORY EFFECT OF MSCS == The pancreata used for clinical islet transplantation are allogeneic and recipients therefore require immunosuppressive drugs to prevent rejection. Recently, Solari et al[23] demonstrated that MSCs could promote the prolonged survival of allograft islets in a rat model with limited treatment with immunosuppressive brokers. Allogeneic islets transplanted to diabetic rats with syngeneic MSCs Tartaric acid survived for over one month whilst islets transplanted alone survived for only seven days. They also demonstrated prolonged graft survival of allogeneic islets transplanted with allogeneic MSCs compared to allogeneic islets transplanted alone. T cell Tartaric acid production of interferon (IFN)- and tumor necrosis factor (TNF)- was decreased in allogeneic islets transplanted with syngeneic MSCs. Furthermore,in vitrostudies of cocultured MSCs and islets generated interleukin (IL)-10 which inhibited CD4+T cells. Melzi et al[20] performed allogeneic islet and allogeneic neural stem cell (NSC) transplantation in a murine model and showed significantly longer graft survival in allogeneic islet/NSC transplanted mice in the absence of immunosuppression, compared to mice transplanted with islets alone (> 100 d Tartaric acid survival). Intriguingly, they detected expansion of regulatory T cells in the spleen of co-transplanted mice. These results indicate that MSCs exert an immunomodulatory role and can actively limit the rejection of co-transplanted islets. The mechanism underlying the immunomodulatory effect of MSCs is likely to be multifactorial and result from the communication between various immune cells and cytokine generation (Determine1). For example, MSCs can inhibit the proliferation and cytotoxicity of resting natural killer (NK) cells, which are key effector cells of the innate immune system and play an important role in antiviral and anti-tumor immune.