Abstract
The human placenta maintains pregnancy and supports the developing fetus by providing nutrition, gas-waste exchange, hormonal regulation, and an immunological barrier from the maternal immune system. The villous syncytiotrophoblast carries most of these functions and provides the interface between the maternal and fetal circulatory systems. The syncytiotrophoblast is generated by the biochemical and morphological differentiation of underlying cytotrophoblast progenitor cells. The dysfunction of the villous trophoblast development is implicated in placenta-mediated pregnancy complications. Herein, we describe gene modules and clusters involved in the dynamic differentiation of villous cytotrophoblasts into the syncytiotrophoblast. During this process, the immune defense functions are first established, followed by structural and metabolic changes, and then by peptide hormone synthesis. We describe key transcription regulatory molecules that regulate gene modules involved in placental functions. Based on transcriptomic evidence, we infer how villous trophoblast differentiation and functions are dysregulated in preterm preeclampsia, a life-threatening placenta-mediated obstetrical syndrome for the mother and fetus. In the conclusion, we uncover the blueprint for villous trophoblast development and its impairment in preterm preeclampsia, which may aid in the future development of non-invasive biomarkers for placental functions and early identification of women at risk for preterm preeclampsia as well as other placenta-mediated pregnancy complications.
Highlights
The human placenta maintains pregnancy and supports the developing fetus by providing nutrition, gas-waste exchange, hormonal regulation, and an immunological barrier from the maternal immune system [1]
We investigated how these PPE genes are involved in villous trophoblast functions and differentiation, and whether their villous trophoblastic dysregulation may have pathologic significance in preterm preeclampsia
To address the important gaps in our understanding of villous trophoblast developmental pathways and their potential relation to placental disease pathways, especially to the development of preterm preeclampsia, we employed various in silico and in vitro methods and a systems biology approach
Summary
The human placenta maintains pregnancy and supports the developing fetus by providing nutrition, gas-waste exchange, hormonal regulation, and an immunological barrier from the maternal immune system [1] Most of these functions are provided by one particular cell type, the syncytiotrophoblast, which lies at the maternal-fetal interface [1,2,3,4]. During the developmental process of cytotrophoblast differentiation and transformation into the syncytiotrophoblast, there is a parallel loss and gain of cellular functions, such as the production of a set of placenta-specific or placenta-enriched molecules [2,3,14,15,16,17,18] These include peptide and steroid hormones, structural and immune proteins, enzymes, and transcription factors. Among the transcription factors involved in this process, ESRRG [19,43,44], GATA2/3 [19,45,46,47], GCM1 [19,48,49], TEF5 [19,50,51], and TFAP2A/C [8,9,18,19,52,53,54,55,56] have been most thoroughly described
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