The Placental Secretome: Identifying Potential Cross-Talk Between Placenta and Islet β-Cells

Abstract

Background/Aims: Insulin-secreting islet β-cells adapt to the insulin resistance associated with pregnancy by increasing functional β-cell mass, but the placental signals involved in this process are not well defined. In the current study, we analysed expression of G-protein coupled receptor (GPCR) mRNAs in mouse islets and islet GPCR ligand mRNAs in placenta during pregnancy to generate an atlas of potential interactions between the placenta and β-cells to inform future functional studies of islet adaptive responses to pregnancy. Methods: Quantative RT-PCR arrays were used to measure mRNA expression levels of: (i) 342 GPCRs in islets from non-pregnant mice, and in islets isolated from mice on gestational days 12 and 18; (ii) 126 islet GPCR ligands in mouse placenta at gestational days 12 and 18. Results: At gestational day 12, a time of rapid expansion of the β-cell mass, 189 islet GPCR mRNAs were quantifiable, while 79 of the 126 known islet GPCR ligand mRNAs were detectable in placental extracts. Approximately half of the quantifiable placental GPCR ligand genes were of unknown function in β-cells. The expression of some islet GPCR and placental ligand mRNAs varied during pregnancy, with altered expression of both GPCR and ligand mRNAs by gestational day 18. Conclusion: The current study has revealed numerous potential routes for interaction between the placenta and islets, and offers an atlas to inform further functional studies of their roles in adaptive responses to pregnancy, and in the regulation of the β-cell mass.

UCN2: a new candidate influencing pancreatic β-cell adaptations in pregnancy

“…qRT-PCR measurements demonstrated that mRNAs for Crh, Ucn1, Ucn2 and Ucn3 were all expressed by mouse placenta at day 18 at similar levels (Fig. 3A), confirming our previous observations (Drynda et al 2018). Furthermore, all four peptides were detected in the peripheral circulation, with UCN2 being the most abundant circulating CRHR agonist (Fig.…”

“…Isolated female islets from non-pregnant and pregnant (day 16) mice were immediately snap frozen in liquid nitrogen following purification from the exocrine pancreas for subsequent RNA extraction using RNeasy Mini Kit (Qiagen) and High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems) for cDNA synthesis, as described previously (Drynda et al 2018). Placenta samples were also collected after termination at day 18 of pregnancy and snap frozen.…”

“…During pregnancy, maternal insulin resistance increases and this is compensated for by increases in β-cell mass and enhanced insulin secretory responses to elevations in plasma glucose (Xue et al 2010, Pasek & Gannon 2013, Baeyens et al 2016. We have recently reported an upregulation of Crh, Ucn2 and Ucn3 mRNA expression in mouse placenta on gestational day 12 (Drynda et al 2018), which correlates to the initiation of β-cell adaptations in rodent pregnancy (Rieck & Kaestner 2010). Similarly, in human pregnancy, levels of CRH in the peripheral circulation increase as gestation progresses (Campbell et al 1987, Sasaki et al 1987 and CRH immunoreactivity has been reported in human placenta (Grino et al 1987), consistent with a placental source for the circulating CRH.…”

Maternal β-Cell Adaptations in Pregnancy and Placental Signalling: Implications for Gestational Diabetes

“…In the context of the pancreatic β-cell, recent research has identified putative pathways for placental crosstalk with the islet in mice [ 62 ]. More specifically, ligands for G-protein coupled receptors that, independent of lactogens, are part of the placental secretome and may be involved in pregnancy-induced adaptive expansion in islets [ 62 ].…”

“…In the context of the pancreatic β-cell, recent research has identified putative pathways for placental crosstalk with the islet in mice [ 62 ]. More specifically, ligands for G-protein coupled receptors that, independent of lactogens, are part of the placental secretome and may be involved in pregnancy-induced adaptive expansion in islets [ 62 ]. Corticotrophin releasing hormone (CRH) receptor was shown to be elevated mid-gestation in islets, and CRH expression was increased at the same time in the placenta; CRH has been shown to mediate insulin secretion [ 63 ] and β-cell proliferation [ 64 ] and could be an important mediator of β-cell adaptation potentially stimulated by placental signalling.…”