ABSTRACT
BACKGROUND: Theoretically human embryonic stem cells (hESCs) have the capacity to self-renew and differentiate into all human cell types. Therefore, the greatest promise of hESCs-based therapy is to replace the damaged tissues of patients suffering from traumatic or degenerative diseases by the exact same type of cells derived from hESCs. Allo-graft immune rejection is one of the obstacles for hESCs-based clinical applications. Human leukocyte antigen (HLA) II leads to CD4+ T cells-mediated allograft rejection. Hence, we focus on optimizing hESCs for clinic application through gene modification. RESULTS: Transcription activator-like effector nucleases (TALENs) were used to target MHC class II transactivator (CIITA) in hESCs efficiently. CIITA(-/-)hESCs did not show any difference in the differentiation potential and self-renewal capacity. Dendritic cells (DCs) derived from CIITA(-/-)hESCs expressed CD83 and CD86 but without the constitutive HLA II. Fibroblasts derived from CIITA(-/-)hESCs were powerless in IFN-γ inducible expression of HLA II. CONCLUSION: We generated HLA II defected hESCs via deleting CIITA, a master regulator of constitutive and IFN-γ inducible expression of HLA II genes. CIITA(-/-)hESCs can differentiate into tissue cells with non-HLA II expression. It's promising that CIITA(-/-)hESCs-derived cells could be used in cell therapy (e.g., T cells and DCs) and escape the attack of receptors' CD4+ T cells, which are the main effector cells of cellular immunity in allograft.
Subject(s)
Humans , Animals , Mice , Nuclear Proteins/genetics , Trans-Activators/genetics , Cell Differentiation/genetics , Gene Deletion , Deoxyribonucleases/metabolism , Human Embryonic Stem Cells/metabolism , Teratoma , Dendritic Cells/metabolism , Immunoglobulins/metabolism , Immunohistochemistry , Membrane Glycoproteins/metabolism , Tumor Cells, Cultured , Histocompatibility Antigens Class II/genetics , Antigens, CD/metabolism , Interferon-gamma/metabolism , Mice, SCID , Reverse Transcriptase Polymerase Chain Reaction , Deoxyribonucleases/classification , B7-2 Antigen/metabolism , Embryoid Bodies/metabolism , Real-Time Polymerase Chain Reaction , Karyotype , Fibroblasts/metabolism , Cell Self Renewal , Antigen-Presenting Cells/metabolismABSTRACT
Objective To investigate the prevalence of low T3 syndrome in patients with acute myocardial infarction(AMI) and explore the effect of low T3 syndrome on outcome of AMI.MethodsThree hundred and thirty-eight patients with AMI admitted to cardiac care unit(CCU) underwent examinations of thyroid function and cardial ultrasound,and were further categorized according to thyroid hormone profile.The records of noninvasive bi-level positive airway pressure(BiPAP)ventilation utilization,length of hospital stay,mortality during hospitalization were evaluated,and the related factors were analysed.ResultsOne hundred and thirty-nine of the 338 patients(41.12%) with AMI complicated with low T3 syndrome.Free triiodothyronine(FT3) was the independent influential factor for length of hospital stay.Low FT3 was significantly correlated with noninvasive BiPAP ventilation utilization and mortality during hospitalization.The average time of follow-up was(21.4?8.1) months.It was revealed by multivariate Cox regression analysis that FT3 was the chief predictor for cumulative death(risk ratio,4.25;95% confidential interval,2.30-7.87),followed by age and left ventricular ejection fraction.ConclusionThe recognition of AMI complicated with low T3 syndrome plays an important role in predicting the disease severity and outcome.