IntroductionBone marrow (BM)-derived mesenchymal stem cells (MSCs) are rare residents of the BM microenvironment. 1 Isolated from their BM companions by their characteristic adherence to plastic, MSCs can be expanded from a single BM aspiration to produce millions of cells. 2 In addition to their powerful replicative capacity, MSCs are multipotential and capable of differentiating into osteocytes, chondrocytes, adipocytes, myocytes, endotheliocytes, and neurocytes. 3,4 Immunologically, MSCs have unique immunologic characteristics, such as low immunogenicity and immunoregulatory property. 5 They express negligible levels of major histocompatibility complex (MHC) class I and no MHC class II or Fas ligand, nor do they express CD80, CD86, CD40, or CD40L. 1,2 MSCs have also been reported to inhibit T-cell proliferation induced in a mixed lymphocyte reaction (MLR) or by nonspecific mitogens. 6 Dendritic cells (DCs), the most potent antigen-presenting cells (APCs), are pivotal and ubiquitously distributed in immune response. They are derived from CD34 ϩ BM stem cells and can be generated from monocytes in vitro by incubation with granulocytemacrophage colony stimulating factor (GM-CSF) and interleukin-4 (IL-4). 7 DCs plays a major role in the uptake, transport, and presentation of antigens with the unique capacity to stimulate naive T cell. 8 The ability of DCs to initiate an immune response depends on its transition from antigen processing to antigen-presenting cell, during which it up-regulates MHC class II and costimulatory molecules (CD80 and CD86) on the cell surface, a process referred to as DC maturation. 9 This transition is indispensable for mounting an immune response because immature DCs (imDCs) not only fail to prime T cells effectively 10 but also serve to promote tolerance induction. 11 In addition to their polarizing capacity on naive T cells, they can interact with B cells 12 and natural killer (NK) cells. 13 Notch is an evolutionarily conserved transmembrane protein that was first described as the product of a neurogenic gene in Drosophila. Vertebrate notch homologs have now been identified in various tissues, which play a critical role not only in embryogenesis, but also in the regulation of cell growth and differentiation of adult tissues. 14 There are 4 identified notch receptors (Notch1-4) and 5 ligands of the Jagged families (Jagged1, 2) and Delta-like families 3,4), but the precise functions of each ligand for receptor are not well understood. 15,16 Many studies have implicated functions of notch signaling in hematopoiesis and thymic development, 17,18 that determine all the choices between 19 between TCR␣ and TCR␥␦ decision 20 and between CD4 ϩ and CD8 ϩ T-cell production. 21 Moreover, they also play an essential role in the peripheral immune regulation. Hoyne et al observed that murine DCs overexpressed Serrate-1 (the homolog of the human Jagged-1) could generate antigen-specific regulatory T cell that transferred tolerance to naive recipient mice. 22 Ohishi et al also demonstrated that the...
Suppression of immune response by mesenchymal stem/stromal cells (MSCs) is well documented. However, their regulatory effects on immune cells, especially regulatory dendritic cells, are not fully understood. We have identified a novel Sca-1+Lin−CD117− MSC population isolated from mouse embryonic fibroblasts (MEF) that suppressed lymphocyte proliferation in vitro. Moreover, the Sca-1+Lin−CD117− MEF-MSCs induced hematopoietic stem/progenitor cells to differentiate into novel regulatory dendritic cells (DCs) (Sca-1+Lin−CD117− MEF-MSC–induced DCs) when cocultured in the absence of exogenous cytokines. Small interfering RNA silencing showed that Sca-1+Lin−CD117− MEF-MSCs induced the generation of Sca-1+Lin−CD117− MEF-MSC–induced DCs via IL-10–activated SOCS3, whose expression was regulated by the JAK–STAT pathway. We observed a high degree of H3K4me3 modification mediated by MLL1 and a relatively low degree of H3K27me3 modification regulated by SUZ12 on the promoter of SOCS3 during SOCS3 activation. Importantly, infusion of Sca-1+CD117−Lin− MEF-MSCs suppressed the inflammatory response by increasing DCs with a regulatory phenotype. Thus, our results shed new light on the role of MSCs in modulating regulatory DC production and support the clinical application of MSCs to reduce the inflammatory response in numerous disease states.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies with an extremely poor prognosis. Energy metabolism reprogramming, an emerging hallmark of cancer, has been implicated in the tumorigenesis and development of pancreatic cancer. In addition to well-elaborated enhanced glycolysis, investigating the role of reprogramming of amino acid metabolism has sparked great interests in recent years. The rewiring amino acid metabolism orchestrated by genetic alterations contributes to pancreatic cancer malignant characteristics including cell proliferation, invasion, metastasis, angiogenesis and redox balance. In the unique hypoperfused and nutrient-deficient tumor microenvironment (TME), the interactions between cancer cells and stromal components and salvaging processes including autophagy and macropinocytosis play critical roles in fulfilling the metabolic requirements and supporting growth of PDAC. In this review, we elucidate the recent advances in the amino acid metabolism reprogramming in pancreatic cancer and the mechanisms of amino acid metabolism regulating PDAC progression, which will provide opportunities to develop promising therapeutic strategies.
Digestive cancers are the leading cause of cancer-related death worldwide and have high risks of morbidity and mortality. Histone methylation, which is mediated mainly by lysine methyltransferases, lysine demethylases, and protein arginine methyltransferases, has emerged as an essential mechanism regulating pathological processes in digestive cancers. Under certain conditions, aberrant expression of these modifiers leads to abnormal histone methylation or demethylation in the corresponding cancer-related genes, which contributes to different processes and phenotypes, such as carcinogenesis, proliferation, metabolic reprogramming, epithelial-mesenchymal transition, invasion, and migration, during digestive cancer development. In this review, we focus on the association between histone methylation regulation and the development of digestive cancers, including gastric cancer, liver cancer, pancreatic cancer, and colorectal cancer, as well as on its clinical application prospects, aiming to provide a new perspective on the management of digestive cancers.
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