VTCN1 regulation of MHC in early human placental development

VTCN1 对人类早期胎盘发育中 MHC 的调节

• 批准号: 10092932
• 负责人: Toshihiko Ezashi
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-31 至 2022-07-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092932
• 关键词: Abbreviations; Abnormal placentation; Address; Affect; Aggressive behavior; Allogenic; Allografting; BMP4; Binding; Blood group antigen f; Cell Proliferation; Cell model; Cell surface; Cells; Cervix Neoplasms; Characteristics; Clinical; Complex; DNA Binding Domain; Decidua; Detection; Development; Disease; Dissection; Down-Regulation; Endometrial Neoplasms; Ensure; Environment; Ethics; Event; Fetal Development; Fetal Growth Retardation; Fetus; First Pregnancy Trimester; Genetic Transcription; HLA Antigens; Hepatitis B e Antigens; Histocompatibility Antigens; Histocompatibility Antigens Class II; Human; Human Chorionic Gonadotropin; Immune; Immunocompetent; Immunohistochemistry; Immunologics; Immunology; Implant; In Vitro; Invaded; Knowledge; Learning; Logistics; MAP Kinase Gene; MHC class II transactivator protein; Major Histocompatibility Complex; Malignant Neoplasms; Maternal-Fetal Exchange; Messenger RNA; Mitogen-Activated Protein Kinases; Modeling; Mothers; Normal tissue morphology; Nucleotides; Pathway interactions; Pattern; Physiological; Placenta; Placentation; Play; Post-Transcriptional Regulation; Pre-Eclampsia; Pregnancy; Pregnancy Rate; Pregnancy loss; Premature Birth; Process; Prognosis; Proteins; Regimen; Regulation; Regulatory Element; Reproductive Immunology; Research; Risk; Role; SET Domain; Sampling; Second Pregnancy Trimester; Small Interfering RNA; Surface; Syncytiotrophoblast; T-Cell Activation; T-Cell Receptor; TCR Activation; Testing; Tissues; Trans-Activators; Undifferentiated; VTCN1 gene; Vascularization; beta-2 Microglobulin; cancer cell; cytotrophoblast; early pregnancy; early pregnancy loss; embryonic stem cell; healthy pregnancy; human embryonic stem cell; human tissue; implantation; improved; in vitro Model; induced pluripotent stem cell; inhibitor/antagonist; innovation; knock-down; matrigel; member; neovascularization; novel; novel diagnostics; novel therapeutics; ovarian neoplasm; overexpression; pancreatic neoplasm; pathogen; pregnancy disorder; programmed cell death ligand 1; protein expression; receptor; response; selective expression; stem cell differentiation; stem cell model; stem cells; tool; trophoblast; tumor; tumor immunology; tumor-immune system interactions

Improper peri-implantation placental development may contribute to feto-maternal diseases (preterm birth, intrauterine growth retardation, preeclampsia) and high rates of pregnancy loss. Since these events occur prior to clinical detection of pregnancy, studies of very early human placental development are ethically and logistically constrained. The proposed project uses an innovative human embryonic stem cell (hESC)-derived model to study primitive trophoblast in vitro. The placenta resembles a cancer in that an implanting fetus and a developing cancer both involve host tissue invasion, massive cellular proliferation, neo-vascularization, and alterations in the immediate immune microenvironment. The placenta of the implanting fetus is one of the only non-cancerous tissues that displays physiologic downregulation of the classical major histocompatibility complex (MHC) class I (MHC-I) transplantation antigens, human leukocyte antigens (HLA)-A and -B. While positive regulatory elements for MHC class II regulation are described, little is known about such regulation of MHC class I expression in noncancerous tissues, including the placenta. Human embryonic stem cells (hESCs) have been used in a novel in vitro model of the stages of human placental development that occur prior to clinical detection of pregnancy. Several mRNAs and proteins that are selectively expressed at high levels in early pregnancy have been identified by using the model. Of those studied, all appear to play roles in invasion. Remarkably, siRNA silencing of one of these proteins, V-Set Domain Containing T Cell Activation Inhibitor 1 (VTCN1), in our model for early trophoblast strongly up-regulated the expression of the MHC class I human leukocyte antigens (HLA)-A and -B, which are normally not expressed in human trophoblast, slightly up-regulated the normally resident HLA-C, but had no effect on expression of the placenta-specific HLA-G. VTCN1 is recognized as a member of the B7 superfamily of cell-surface co-receptors that regulate T cell receptor interactions with MHC molecules. It has been postulated that VTCN1 neo-expression affects cancer cells’ ability to evade host immune detection. These results highlight the efficacy of our in vitro models for filling several important knowledge gaps. The unique ability to model peri-implantation placental development in vitro will enable dissection of the control of MHC-I expression on human trophoblast (TB), particularly testing the hypothesis that the lack of expression of HLA-A and -B by TB is controlled by VTCN1 through largely indirect mechanisms. There are three aims to the proposal: 1) Demonstrate classical MHC class I suppression by VTCN1 in various TB models, including hESC-derived primitive trophoblast, by using VTCN1 knock-down and overexpression; 2) Define the transcriptional pathways and transcriptional and immediate post-transcriptional regulation involved in VTCN1-related alterations in TB MHC-I expression and 3) Identify protein partners of VTCN1 in in vitro cell models of early TB to discover and confirm pathways involved in VTCN1 regulation of MHC class I expression. These studies will have application to the origins of common disorders of abnormal placentation and to the understanding of cancer immunology.

不适当的植入期胎盘发育可能导致胎母疾病（早产、宫内）