Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Cvitic, S.
In utero programming of human feto-placental cells: The link to fetal developmental programming and disease susceptibility in adulthood
[ Dissertation ] Medical University of Graz; 2013. pp. 103
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- Autor*innen der Med Uni Graz:
- Tokic Silvija
- Betreuer*innen:
- Desoye Gernot
- Frank Sasa
- Lang-Olip Ingrid
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- Abstract:
- The `Developmental Origin of Health and Disease¿ (DOHaD) hypothesis holds that an adverse maternal environment during the intrauterine development of an individual has great influence on adult phenotype and disease development in adulthood. As a multifunctional organ that synthesizes, metabolizes, and transports nutrients to the fetus, the placenta influences maternal, placental and fetal metabolism. Hence, it determines the course of fetal development and plays a key role in fetal programming. Epigenetic mechanisms bear the potential for gene regulation upon environmental stimuli and are, thus, a crucial factor in the pathogenesis of complex disorders characterized by sexual dimorphism in their prevalence and severity. The current thesis investigated the intrauterine programming of the feto-placental cells by gestational diabetes mellitus (GDM), whereby endothelial cells from two distinct vascular beds, arterial (AEC) and venous endothelial cells (VEC) were used. The cellular batch was further extended by adding cytotrophoblasts (CT) and syncytiotrophoblast (SCT) when investigating fetal sex influence on placental gene expression. Primary AEC isolated from human term placentas after GDM pregnancies (diabetic AEC) under identical culture conditions differ in their functional characteristics, i.e. proliferation and network formation, from cells isolated after healthy pregnancies (normal AEC). Genome-wide DNA methylation and transcription profile of normal and diabetic AEC and VEC clearly show individual diabetic signatures accentuating and potentially explaining the observed functional differences. All four cell types analyzed in vitro varied in the extent of sex-biased gene expression, despite the fact that these cells originate from the same organ. Overall, the data reveal that GDM-derived feto-placental endothelial cells persistently differ from cells isolated from uncomplicated pregnancies. This demonstrates that the placental endothelial cells in vitro remember their diabetic in vivo phenotype. Furthermore, the observed differences in gene expression and functional differences between male and female feto-placental cells argue for an intrinsic program that enables cells to remember fetal sex. Hence, this thesis introduces new evidence of cellular memory and intrinsic cellular changes depending on the in utero exposure to the adverse maternal environment i.e. GDM, affected placental vascular bed i.e arterial vs. venous, and fetal sex. It is plausible that these intrinsic changes in utero contribute to altered disease susceptibility in adulthood.