Thursday, November 21, 2024
11/21/2024
Project Summary The placenta performs important functions to ensure proper development of the fetus, including oxygen and nutrients exchange, waste product removal and hormone secretion. It also acts as a barrier to protect the fetus from harmful substances and pathogens that might be present in the maternal circulation. Despite its short lifespan, the placenta plays a critical role in the survival and growth of the fetus. Implantation failure and inadequate placental development can lead to pregnancy complications, such as preeclampsia, miscarriage, and fetal growth restriction. However, our understanding of human placenta development is quite limited due to scarcity of fetal tissues, ethical restrictions and lack of practical experimental tools. Our preliminary studies show that human trophoblast stem cells (hTSCs) possess an intrinsic self- organization property. When a colony of hTSCs starts to cluster, they spontaneously form an organoid with cavities resembling trophoblastic lacunae, and can continuously develop into a multicellular tissue resembling first-trimester placental villi under a neuregulin 1 (NRG1) stimulation. In this proposed research, we will undertake an exploratory, high-risk but high-reward study to generate a microfluidic human placenta model. Specifically, we will derive hTSCs from human induced pluripotent stem cells (hiPSCs) through a naïve pluripotency stage. We will then use these hTSCs to generate microfluidic placenta organoids. The role of YAP signaling in regulating spontaneous syncytiotrophoblast (STB) differentiation will be examined. We will further induce the development of placental villus-like tissue by modulating timing and concentration of NRG1, and examine morphologies and cell composition of the resultant placenta organoids. Important, we will conduct single-cell RNA sequencing (scRNA-seq) analysis on the resultant placental villus-like tissue at different times and perform transcriptome-wide comparisons with published in vivo human placenta scRNA-seq datasets. This hTSC- derived human placenta organoid system will offer the first-of-its-kind experimental platform for studying previously elusive stages of human placental development. This research, if successful, will lead to innovative technologies and methodologies for controllable, reproducible, and scalable manufacturing of in vitro stem cell-derived tissues with molecular and cellular characteristics consistent with the early/mid-gestation placenta. This platform can also serve as a screening tool to investigate the potential negative effects of pathogens, drugs or toxic substances on human placental development, which will accelerate research efforts towards early diagnosis, prevention and treatment of pregnancy complications associated with insufficient or abnormal placentation.
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