Insulin control of placental gene expression shifts from mother to foetus over the course of pregnancy

Abstract

Aims/hypothesis: The human placenta is a complex organ situated at the interface between mother and foetus that separates maternal from foetal blood. The placental surfaces exposed to the two bloodstreams are different, i.e. trophoblasts and endothelial cells are in contact with the maternal and foetal circulation, respectively. Both cell types produce high insulin receptor levels. The aim of the present study was to test the hypothesis that spatiotemporal changes in insulin receptor expression in trophoblasts from first trimester to the endothelium at term shift the control of insulin-dependent processes from mother to foetus. Methods: Global microarray analysis of primary trophoblasts from first trimester and term human placentas and endothelial cells from term human placentas cultured under hyperinsulinaemic and control conditions identified different sets of regulated genes in trophoblasts and endothelial cells. Results: Insulin effects on placental gene expression underwent developmental changes from trophoblasts in the first trimester to endothelial cells at term that were paralleled by changes in levels of activated insulin receptors. The changes in gene regulation were both quantitative (i.e. magnitude of effect) and qualitative (i.e. specific genes affected and direction of regulation). Conclusions/interpretation: This spatio-temporal shift in insulin sensitivity throughout pregnancy allows maternal and foetal insulin to regulate different processes within the placenta at different gestational stages, facilitated by compartmentalisation of the insulin response. Thus, by altering the levels and function of insulin receptors in space and time, control of insulin-dependent processes in the human placenta will change from mother to foetus throughout gestation. This will be of particular interest in conditions associated with altered maternal or foetal insulin levels, i.e. diabetes mellitus or intrauterine growth restriction.

The Placenta as a Mediator of Stress Effects on Neurodevelopmental Reprogramming

“…The placenta expresses receptors for numerous hormones including glucocorticoids, insulin, insulin-like growth factors (IGFs), leptin, gonadal hormones, cytokines, and prostaglandins (Bodner et al, 1999;Fowden et al, 2014;Hiden et al, 2006;Keelan and Mitchell, 2007;McCormick et al, 1981;Unlugedik et al, 2010). These signals are integrated by downstream cascades that ultimately influence placental growth, energy homeostasis, and endocrine action.…”

Regulation of Placental Growth Hormone Secretion in a Human Trophoblast Model—The Effects of Hormones and Adipokines

“…PGH can cause insulin resistance by changing the subunit composition of phosphatidylinositol 3-kinase17 (11). The contribution of PGH to maternal insulin resistance makes it tempting to hypothesize a maternalplacental feedforward-feedback loop as proposed recently (28). In this model, elevated insulin levels associated with insulin resistance would lead to a reduced PGH secretion, a contributing factor to this condition, which in turn would alleviate insulin resistance.…”

“…BeWo cells were generously donated by Prof. R Mortimer's laboratory at the Royal Brisbane and Women's Hospital in Brisbane and were originally purchased from the American Tissue Culture Collection (ATCC, Rockville, MD; ATCC no. CCL98; used at passages [25][26][27][28][29][30]. Reagents for cell culture were supplied by Invitrogen Life Technologies (Sydney, Australia).…”

MT1-MMP Expression in First-Trimester Placental Tissue Is Upregulated in Type 1 Diabetes as a Result of Elevated Insulin and Tumor Necrosis Factor-α Levels

“…Total RNA from 10 first-trimester trophoblast preparations isolated from different placentas was pooled, and 5 g RNA was prepared for hybridization as described previously (35). For expression analysis, cRNA was hybridized against HU133A-chips (Affymetrix, Santa Clara, CA) according to the manufacturer's instructions.…”

“…The primer pairs included splicing sites within the amplicon. Because of its stable expression within the different placental cell types, the mRNA amount of the RPL30 was used as an internal control (35). Two hundred nanograms total RNA was used for the one-step RT-PCR kit from Qiagen (Hilden, Germany) according to the manufacturer's instructions.…”