Downregulation of p53 drives autophagy during human trophoblast differentiation

Martin Gauster,Alexander Deutsch,Dagmar Kolb-Lenz,Gernot Desoye,Florian Herse,Sabine Maninger,Monika Siwetz,Ursula Hiden,Andreas Prokesch,Amin El-Heliebi

doi:10.1007/s00018-017-2695-6

Abstract

The placental barrier is crucial for the supply of nutrients and oxygen to the developing fetus and is maintained by differentiation and fusion of mononucleated cytotrophoblasts into the syncytiotrophoblast, a process only partially understood. Here transcriptome and pathway analyses during differentiation and fusion of cultured trophoblasts yielded p53 signaling as negative upstream regulator and indicated an upregulation of autophagy-related genes. We further showed p53 mRNA and protein levels decreased during trophoblast differentiation. Reciprocally, autophagic flux increased and cytoplasmic LC3B-GFP puncta became more abundant, indicating enhanced autophagic activity. In line, in human first trimester placenta p53 protein mainly localized to the cytotrophoblast, while autophagy marker LC3B as well as late autophagic compartments were predominantly detectable in the syncytiotrophoblast. Importantly, ectopic overexpression of p53 reduced levels of LC3B-II, supporting a negative regulatory role on autophagy in differentiating trophoblasts. This was also shown in primary trophoblasts and human first trimester placental explants, where pharmacological stabilization of p53 decreased LC3B-II levels. In summary our data suggest that differentiation-dependent downregulation of p53 is a prerequisite for activating autophagy in the syncytiotrophoblast.

Highlights

The placenta is responsible for pregnancy-maintaining functions, such as exchange of gases and metabolites, secretion of essential hormones, and regulation of water balance
Together they form a major part of the placental barrier, which is maintained by a unique cellular turnover: a small subset of mitotically active progenitors among the cytotrophoblast population divides in an asymmetric way, generating one daughter cell with a preserved proliferation-competent status and a second that escapes the cell cycle
Once trophoblasts undergo differentiation and fuse with the multinucleated syncytium, p53 levels decline while autophagic activity increases

Summary

Introduction

The placenta is responsible for pregnancy-maintaining functions, such as exchange of gases and metabolites, secretion of essential hormones, and regulation of water balance. Placental villi are covered by a continuous layer of a multinucleated trophoblast, referred to as syncytiotrophoblast, and underlying mononucleated cytotrophoblasts Together they form a major part of the placental barrier, which is maintained by a unique cellular turnover: a small subset of mitotically active progenitors among the cytotrophoblast population divides in an asymmetric way, generating one daughter cell with a preserved proliferation-competent status and a second that escapes the cell cycle. These post-mitotic cells undergo differentiation and fuse with the syncytiotrophoblast. Upon fusion, isolated short fragments of plasma membrane can be observed within the syncytioplasm and are presumably recycled in due time [4]

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