Placental Organoids for Modeling and Treating Preeclampsia

用于建模和治疗先兆子痫的胎盘类器官

• 批准号: 10464766
• 负责人: S. Ananth Karumanchi
• 金额: $ 4.9万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2022-12-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10464766
• 关键词: 3-Dimensional; Abnormal placentation; Activities of Daily Living; Address; Angiogenic Proteins; Binding; Blood Circulation; Blood Vessels; Cardiovascular system; Cell Culture System; Cell Line; Cells; Cellular biology; Cerebral Palsy; Cessation of life; Chromosome 13; Clinical; Data; Defect; Development; Developmental Process; Discipline of obstetrics; Disease; Drug Screening; Eclampsia; Embryonic Development; Endothelial Growth Factors Receptor; Epithelial; Etiology; Event; Exhibits; FLT1 gene; Fetus; Fibroblasts; First Pregnancy Trimester; Genes; Genetic; Goals; Greater sac of peritoneum; HELLP Syndrome; Human; Hypertension; Hypoxia; Immunocompromised Host; Impairment; Implant; Ischemia; Kidney Failure; LTK gene; Laboratories; Lead; Length; Maternal complication; Mediating; Membrane; Methods; Modeling; Monoclonal Antibodies; Mothers; Mus; Neonatal Mortality; Nervous System Trauma; Nude Mice; Organ; Organoids; Patau' s syndrome; Pathogenesis; Pathologic; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiology; Placenta; Placentation; Plant Roots; Population; Pre-Eclampsia; Pregnancy; Premature Birth; Primates; Protein Isoforms; Proteinuria; Protocols documentation; Rapid screening; Regenerative Medicine; Reproducibility; Research Personnel; Risk; Rodent; Seizures; Signal Transduction; Signs and Symptoms; Small for Gestational Age Infant; Specimen; Stroke; Structure; Syncytiotrophoblast; Syndrome; Testing; Time; Tissues; Uterus; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Villous; Woman; biomarker development; cell type; cytotrophoblast; early onset; endothelial dysfunction; epidemiology study; experimental study; fetal; functional disability; human model; improved; in vivo evaluation; induced pluripotent stem cell; infancy; neonatal morbidity; new therapeutic target; nonhuman primate; novel; novel therapeutics; precision medicine; pregnancy disorder; receptor; self-renewal; stem cell population; stem cells; therapeutic candidate; therapeutic evaluation; three dimensional cell culture; trophoblast; 3-Dimensional; Abnormal placentation; Activities of Daily Living; Address; Angiogenic Proteins; Binding; Blood Circulation; Blood Vessels; Cardiovascular system; Cell Culture System; Cell Line; Cells; Cellular biology; Cerebral Palsy; Cessation of life; Chromosome 13; Clinical; Data; Defect; Development; Developmental Process; Discipline of obstetrics; Disease; Drug Screening; Eclampsia; Embryonic Development; Endothelial Growth Factors Receptor; Epithelial; Etiology; Event; Exhibits; FLT1 gene; Fetus; Fibroblasts; First Pregnancy Trimester; Genes; Genetic; Goals; Greater sac of peritoneum; HELLP Syndrome; Human; Hypertension; Hypoxia; Immunocompromised Host; Impairment; Implant; Ischemia; Kidney Failure; LTK gene; Laboratories; Lead; Length; Maternal complication; Mediating; Membrane; Methods; Modeling; Monoclonal Antibodies; Mothers; Mus; Neonatal Mortality; Nervous System Trauma; Nude Mice; Organ; Organoids; Patau' s syndrome; Pathogenesis; Pathologic; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiology; Placenta; Placentation; Plant Roots; Population; Pre-Eclampsia; Pregnancy; Premature Birth; Primates; Protein Isoforms; Proteinuria; Protocols documentation; Rapid screening; Regenerative Medicine; Reproducibility; Research Personnel; Risk; Rodent; Seizures; Signal Transduction; Signs and Symptoms; Small for Gestational Age Infant; Specimen; Stroke; Structure; Syncytiotrophoblast; Syndrome; Testing; Time; Tissues; Uterus; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Villous; Woman; biomarker development; cell type; cytotrophoblast; early onset; endothelial dysfunction; epidemiology study; experimental study; fetal; functional disability; human model; improved; in vivo evaluation; induced pluripotent stem cell; infancy; neonatal morbidity; new therapeutic target; nonhuman primate; novel; novel therapeutics; precision medicine; pregnancy disorder; receptor; self-renewal; stem cell population; stem cells; therapeutic candidate; therapeutic evaluation; three dimensional cell culture; trophoblast

While the underlying etiology of preeclampsia (a hypertensive disorder of pregnancy) is not known, the disease starts with shallow placentation and placental ischemia which in turn releases excess of anti-angiogenic proteins such as soluble fms-like tyrosine kinase 1 (sFLT1) in the mother's bloodstream that is responsible for the systemic maternal endothelial dysfunction. Self-renewing 3D epithelial organoids that closely resemble the structure and physiology of the original organ have been successfully developed into various tissue types using human induced pluripotent stem cells (hiPSCs). However, organoids of the human placental trophoblasts using hiPSCs are yet to be generated. Our goal of this proposal is to generate trophoblast organoids from disease-specific hiPSCs to study preeclampsia pathogenesis and to screen for drugs as potential treatment targets. We will generate a new model of trophoblast organoid using hiPSCs, replicating the early stage of gestation from normal and preeclamptic pregnancies, a time in development that has – until now – has been mostly inaccessible to researchers. In aim 1, we will optimize trophoblast organoid protocols in our laboratory using hiPSCs derived trophoblast differentiation method from donor fibroblasts and will confirm that these organoids phenotypically and functionally behave like first trimester villous tissue. We will then test the hypothesis that the functional capacity of trophoblast organoids derived from hiPSCs obtained from early-onset preeclampsia will be impaired when compared to trophoblast organoids derived from non-hypertensive controls. In aim 2, we will model maternal syndrome of preeclampsia in nude mice with factors made by human placenta. To model human preeclampsia, we will generate trophoblast organoids using hiPSCs derived from placental fibroblasts from women carrying a fetus with trisomy 13, a disorder characterized by 10-fold excess risk of preeclampsia due to extra copy of sFLT1 gene from chromosome 13. We will then test in vivo efficacy of monoclonal antibodies that target the unique C-terminus of human sFLT1-i14 (the isoform that is primate-specific) for enhanced clearance of sFLT1 from systemic circulation. Due to the organoid's ready access and ability to replicate the early stages of development from well-characterized cells, the trophoblast organoid model promises to significantly improve our understanding of preeclampsia and provides rapid screening methods for testing potential drugs and furthering precision medicine methods in obstetrics.

虽然先兆子痫的潜在病因（一种高血压疾病） 尚不清楚，该疾病始于浅置放置和占地缺血 转弯释放超过抗血管生成蛋白，例如固体FMS样酪氨酸激酶1 （SFLT1）在母亲的血液中，负责系统性材料内皮 功能障碍。自我更新3D上皮器官，与结构非常相似 原始器官的生理学已成功发展为各种组织 使用人类诱导多能干细胞（HIPSC）的类型。但是， 使用HIPSC的人胎盘滋养细胞尚未产生。我们的目标 提案是从疾病特异性hipscs产生滋养细胞的器官来研究 先兆子痫的发病机理并筛选药物作为潜在的治疗靶标。我们 将使用HIPSC生成新的滋养细胞器官模型，并早期复制 妊娠阶段是正常和先兆前怀孕的妊娠期，这是一个发展的时期 到目前为止，研究人员大部分都无法获得。在AIM 1中，我们将优化 我们实验室中使用HIPSC衍生的滋养细胞的滋养细胞器官方案 与供体成纤维细胞的分化方法，并将确认这些器官 表型和功能上的表现就像头三个月的绒毛组织。然后我们将测试 假设从获得的HIPSC衍生的滋养细胞器官的功能能力 与滋养细胞类器官相比 源自非高血压控制。在AIM 2中，我们将建模 裸小鼠的先兆子痫，其因子由人plapeta产生的因素。建模人类 先兆子痫，我们将使用胎盘衍生的HIPSC生成滋养细胞类器官 来自胎儿的女性的成纤维细胞，三体属三体症，这种疾病为特征10倍 由于13染色体的SFLT1基因的额外副本，先兆子痫的风险过多。我们将 然后测试靶向人类独特C末端的单克隆抗体的体内效率 SFLT1-I14（主要特异性的同工型），以增强从 系统性圆圈。由于器官的访问和能力，可以早日复制 特征良好的细胞（滋养细胞）类器官的发育阶段 有望显着提高我们对先兆子痫的理解，并提供快速 测试潜在药物和进一步精确医学方法的筛查方法 在妇产科。