Developing a novel approach to the nonhuman primate placental organoid model

开发非人灵长类胎盘类器官模型的新方法

• 批准号: 10589154
• 负责人: Victoria HJ Roberts
• 金额: $ 26.25万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-10 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589154
• 关键词: 3-Dimensional; Animal Model; Apical; Biological Models; Biopsy; Biopsy Specimen; Blood Vessels; Cell Communication; Cell Differentiation Induction; Cell Differentiation process; Cell Lineage; Cell Polarity; Cell model; Cell surface; Cells; Characteristics; Chorionic Villi Sampling; Clinical; Cues; Decidua; Development; Digestion; Discipline of obstetrics; Epithelium; Equilibrium; Ethics; Extracellular Matrix; Fetal Tissues; First Pregnancy Trimester; Foundations; Functional disorder; Growth; Histologic; Human; In Vitro; Invaded; Investigation; Knowledge; Macaca; Macaca mulatta; Maternal-Fetal Exchange; Mediator; Metabolic; Methodology; Methods; Modeling; Nutritional; Organ; Organoids; Pathway interactions; Phenotype; Placenta; Placentation; Pregnancy; Prenatal Diagnosis; Preparation; Procedures; Process; Property; Protocols documentation; Regulation; Research; Resources; Sampling; Source; Specific qualifier value; Spiral Artery of the Endometrium; Structure; Surface; Suspensions; Syncytiotrophoblast; System; Techniques; Termination of pregnancy; Testing; Time; Tissue Banks; Tissue Model; Tissue Sample; Tissues; Villous; Work; avoid pregnancy; cell dimension; cell type; critical period; experimental study; feasibility testing; fetal; in vitro Assay; in vitro Model; insight; maternal outcome; minimally invasive; nonhuman primate; novel; novel strategies; placental stem cell; pregnant; sample collection; self organization; stem cells; three dimensional structure; tissue culture; tool; trophoblast; trophoblast stem cell; two-dimensional; ultrasound

PROJECT SUMMARY The placenta is the regulatory and exchange barrier that functions to balance maternal nutritional supply with fetal metabolic demands during pregnancy. Inadequate placental development and subsequent dysfunction results in a range of adverse fetal and maternal outcomes. The first trimester is a crucial time for the establishment of appropriate placentation, yet our current knowledge of first trimester development is inadequate, and understanding of placental development and function throughout pregnancy is impeded by the lack of access to longitudinal samples and a lack of suitable in vitro model systems. In early placental formation, trophoblast cells, a specialized placental stem cell, differentiate into two types: extravillous trophoblast cells (EVTs), which invade the maternal spiral arteries, anchor the placenta in the decidua and are critical for forming a strong vascular foundation for a fully functioning placenta. The syncytiotrophoblast (SYN), a multinucleated epithelium, serves as the maternal-fetal exchange surface. Despite their importance, understanding the regulation of trophoblast cell lineage specification and differentiation has been hindered by the lack of appropriate cellular model systems and access to placental tissue from early gestation. Organoids are self-organizing and propagating 3-dimensional (3D) culture model systems that are derived from stem cells. They can be directed to grow ex vivo in to mini organ structures by manipulating growth conditions and providing developmental cues that drive phenotype-specific cell development. Recently, a first trimester human trophoblast organoid system has been developed. However, the placenta is a fetal tissue which leads to ethical concerns associated with the use of termination samples in research. The nonhuman primate (NHP) offers a solution to this problem. We propose to generate a first trimester NHP organoid model, and test the feasibility of obtaining first trimester placenta samples through the use of ultrasound-guided chorionic villous sampling (CVS), thus avoiding the need for termination. A second challenge to the use of organoids for in vitro experiments is cell polarity. Specifically, use of a matrix suspension typically orientates the apical cell surface to the center creating an `inside out' organoid structure, thus limiting their utility in placental barrier studies. Importantly, recent advances in other organoid systems have demonstrated the ability to alter the composition of the extracellular matrix to convert 3D structures to 2D cell layers. The overarching premise of this proposal is to develop a new ex vivo tool to expand our understanding of early placental development and function in a translational animal model. Within the scientific objectives we will utilize CVS to obtain placental biopsies, in addition to whole placental tissue collection for organoid preparations to directly compare the two sampling methodologies. Organoids will be induced to differentiate, and culture conditions manipulated to alter cell polarity. This novel work will establish a pipeline for previously inaccessible pathways for the study of normal and perturbed placental function.

项目总结