Placental secretome characterization identifies candidates for pregnancy complications

Tina Napso,Amy L George,Amanda N Sferruzzi-Perri,Russell S Hamilton,Claire L Meek,Ionel Sandovici,Frank Reimann,Fiona M Gribble,Richard G Kay,Xiaohui Zhao,Marta Ibañez Lligoña

doi:10.1038/s42003-021-02214-x

Abstract

Alterations in maternal physiological adaptation during pregnancy lead to complications, including abnormal birthweight and gestational diabetes. Maternal adaptations are driven by placental hormones, although the full identity of these is lacking. This study unbiasedly characterized the secretory output of mouse placental endocrine cells and examined whether these data could identify placental hormones important for determining pregnancy outcome in humans. Secretome and cell peptidome analyses were performed on cultured primary trophoblast and fluorescence-activated sorted endocrine trophoblasts from mice and a placental secretome map was generated. Proteins secreted from the placenta were detectable in the circulation of mice and showed a higher relative abundance in pregnancy. Bioinformatic analyses showed that placental secretome proteins are involved in metabolic, immune and growth modulation, are largely expressed by human placenta and several are dysregulated in pregnancy complications. Moreover, proof-of-concept studies found that secreted placental proteins (sFLT1/MIF and ANGPT2/MIF ratios) were increased in women prior to diagnosis of gestational diabetes. Thus, placental secretome analysis could lead to the identification of new placental biomarkers of pregnancy complications.

Highlights

Alterations in maternal physiological adaptation during pregnancy lead to complications, including abnormal birthweight and gestational diabetes
The placenta produces a wide variety of cytokines throughout pregnancy, which contribute to the low-grade systemic inflammation and induction of maternal insulin resistance that normally occurs in the second half of pregnancy and some data suggest that placental cytokine production is aberrant in women with poor pregnancy outcomes like PE, gestational diabetes mellitus (GDM), and IUGR5
We performed mass spectrometry on three types of samples: (1) primary cultures containing mouse placental endocrine cells, (2) conditioned media from primary cultures of mouse placental endocrine cells, and (3) endocrine cells isolated from the mouse placenta by fluorescence-activated cell sorting (FACS)

Summary

Introduction

Alterations in maternal physiological adaptation during pregnancy lead to complications, including abnormal birthweight and gestational diabetes. Transcriptomic analyses have informed on the repertoire of hormones expressed by the human placenta in healthy and complicated pregnancies[9,10,11,12] These studies are conducted mainly on samples obtained at delivery and involve analysis of pieces of placenta tissue, which is heterogeneous in nature and includes trophoblast, vascular, stromal, and specialized immune cell types. The junctional zone is discrete from, and forms under distinct genetic instruction to, the labyrinthine zone, which performs substrate transport function in the mouse placenta This is in contrast to humans, where the endocrine and transport functions of the placenta are carried out by the same region/cell type, the syncytiotrophoblast (STB), preventing the specific, sole examination of placental hormone production. Many gene and protein networks regulating placental development and function overlap in the two species[14,15]

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