Human PZP and common marmoset A2ML1 as pregnancy related proteins

Hirofumi Kashiwagi,Asako Otomo,Hitoshi Ishimoto,Kou Sakabe,Kazumi Takahashi,Erika Sasaki,Toshiro Seki,Yoshie Kametani,Fuyuki Kametani,Mikio Mikami,Rihito Kinami,Takashi Shiina,Sun-Ichiro Izumi,Noriaki Hirayama

doi:10.1038/s41598-020-61714-8

Abstract

While pregnancy-related proteins (PRP) are known to contribute to immunotolerance during pregnancy, their significance to development of invasive placenta is unclear. We compared PRP expression in humans and the common marmoset (Callithrix jacchus), a new-world monkey. Invasive placenta was observed at the maternal-foetal interface of marmoset placenta from green fluorescent protein (GFP)-expressing foetus and wild type mother. The pregnancy zone protein (PZP) and alpha-2 macroglobulin-like 1 (A2ML1) proteins exhibited the most prominent increase in expression during the second trimester in humans and marmoset, respectively. In humans, PZP accumulated at the maternal-foetal interface and A2ML1 accumulated in the amnion. Similarly, A2ML1 mRNA was detected in marmoset placenta. These proteins belong to the A2M family of protease inhibitors, and both PZP and A2ML1 share around 90% homology between human and marmoset and have highly conserved structures. However, the protease-reacting bait regions of the proteins had lower homology (56.8–60.7% in proteins) relative to the rest of the sequence. Notably, the cleavage site of a proinflammatory proline-endopeptidase was preserved in human PZP and marmoset A2ML1. These proteins contain multiple sites that are cleaved by proteases involving proline-endopeptidase. Systemic regulation of these A2M family proteins may be important in animals with invasive placenta.

Highlights

While pregnancy-related proteins (PRP) are known to contribute to immunotolerance during pregnancy, their significance to development of invasive placenta is unclear
We analysed the structure of full-term marmoset placenta and examined the extent of trophoblast invasion
The concentration of A2M was maintained at high levels without further increase in the second trimester of both human and marmoset pregnancies (Supplemental Table 1). These results suggested that human pregnancy zone protein (PZP) and marmoset alpha-2 macroglobulin-like 1 (A2ML1) have unique but common kinetics in the plasma during pregnancy, the increase varied among individuals

Summary

Introduction

While pregnancy-related proteins (PRP) are known to contribute to immunotolerance during pregnancy, their significance to development of invasive placenta is unclear. It is reported that placental invasion is related to brain growth, as large amounts of oxygen and nutrients may develop larger brains[4,5] This benefit forces the trophoblasts to encounter the mother’s immunity for a long period. Pregnancy-related proteins (PRPs) are molecules whose concentration is increased in maternal circulation during pregnancy[8,9,10] The functions of these proteins are not clearly defined, but it has been speculated that they help to maintain a normal pregnancy by suppressing immune reactions to allogeneic cells or fragments. Pregnancy zone protein (PZP) has been reported to be markedly increased in the maternal sera during pregnancy[17], and binds to a molecule closely related to immunosuppression, transforming growth factor-β (TGF-β)[18,19]. Model systems should be selected and/or developed based on animals with invasive trophoblasts and immune systems more similar to those of humans, which would be more convincing models of human pregnancy

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