Analysis of the local and global responses in the placenta syncytiotrophoblast

About This Grant

ABSTRACT The multinucleated syncytiotrophoblast (STB) is a tissue-sized single cell that separates the maternal and fetal vasculature during pregnancy. The STB wraps around the villous trees of the placenta lobules, encasing them in a cell with billions of nuclei in a common cytoplasm. This giant single cell facilitates the exchange of nutrients, is essential for fetal immunoprotection, is the primary producer of pregnancy hormones, and performs critical metabolic roles. Further, the STB must simultaneously respond to gradients in oxygen, nutrients, maternal hormones, and pathogens that fluctuate in space and time. How does a single cell support these diverse homeostatic tasks and simultaneously respond to local stresses? We hypothesize that the multinucleate organization is fundamental to supporting the many demands of production, metabolism, and stress response required of a single STB cell. Recent work and our preliminary data show that individual nuclei within the STB indeed have distinct transcriptional programs despite all sharing the same cell cytoplasm. This indicates that STB nuclei are heterogeneous in activity and function. Notably, GO terms for each of the STB nuclear clusters show mutually exclusive expression of homeostatic STB functions or stress response genes. Therefore, nuclear individuality could both facilitate the myriad of STB functions and the insulation of the stress response by spatially clustering in different regions depending on local functions or conditions. Major gaps in knowledge include how different nuclear identities are spatially patterned in the tissue, how nuclear identities arise mechanistically, and the functional consequences of nuclear heterogeneity within the STB cell. Spatial organization of the STB is disrupted in multiple forms of preeclampsia, a pregnancy disease that stems from improper placentation in the first trimester or maternal inflammation. We predict that the systemic stress seen in preeclampsia perturbs the functional balance and spatial organization of homeostatic and stress response pathways in STB nuclei. The proposed experiments will analyze heterogeneous gene expression in healthy and preeclamptic placentas with the following aims: Aim 1: Dissect the spatial patterns of RNA expression and localization in the STB cell and Aim 2: Identify the function and mechanism of heterogeneous nuclear gene expression in the STB. We will apply state-of-the-art spatial transcriptomics on placentas from healthy and preeclamptic pregnancies to analyze gene expression patterning in different locations of the STB. Using super-resolution, live-cell imaging, and genetic manipulations of placenta organoids, we will determine the mechanisms generating specialized nuclear transcription and the functional consequences of heterogeneous nuclear gene expression. This work will establish a functional atlas of STB nuclear identity patterning in health and preeclampsia and act as a guide to discover molecular drivers of pregnancy disease.