Senescent Changes and Endoplasmic Reticulum Stress May Be Involved in the Pathogenesis of Missed Miscarriage

Yunhui Tang; Xinyan Zhang; Yi Zhang; Hua Feng; Jing Gao; Haiyan Liu; Fang Guo; Qi Chen

doi:10.3389/fcell.2021.656549

Senescent Changes and Endoplasmic Reticulum Stress May Be Involved in the Pathogenesis of Missed Miscarriage

Front Cell Dev Biol. 2021 Jun 17:9:656549. doi: 10.3389/fcell.2021.656549. eCollection 2021.

Authors

Yunhui Tang¹, Xinyan Zhang², Yi Zhang³, Hua Feng⁴, Jing Gao⁵, Haiyan Liu⁶, Fang Guo⁶, Qi Chen³

Affiliations

¹ Department of Family Planning, The Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China.
² The Institution of Obstetrics and Gynaecology, The Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China.
³ Department of Obstetrics and Gynaecology, The University of Auckland, Auckland, New Zealand.
⁴ Department of Cervical Disease, The Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China.
⁵ Department of Medical Laboratory, The Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China.
⁶ Department of Obstetrics, The Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China.

Abstract

Background: Senescence is involved in many complications of pregnancy. However, whether senescent changes are also associated with missed miscarriage has not been fully investigated.

Methods: The levels of p16, p21, and γH2AX, markers of senescence, were measured in placentas collected from women with missed miscarriage by immunohistochemistry and Western blotting. Levels of misfolded proteins in missed miscarriage placentas or normal first-trimester placenta that had been treated with H₂O₂ (100 μM) or extracellular vesicles (EVs) collected from missed miscarriage placental explant culture were measured by fluorescent compound, thioflavin-T. The production of reactive oxygen species (ROS) by missed miscarriage placentas was measured by CellROX^® Deep Red.

Results: Increased levels of p16, p21, and γH2AX were presented in missed miscarriage placentas compared to controls. Increased levels of misfolded proteins were shown in missed miscarriage placentas, but not in EVs that were collected from missed miscarriage placentas. The ROS production was significantly increased in missed miscarriage placental explant cultures. Increased levels of misfolded proteins were seen in the normal first-trimester placenta that had been treated with H₂O₂ compared to untreated.

Conclusion: Our data demonstrate that there are increases in senescence and endoplasmic reticulum stress and ROS production in missed miscarriage placenta. Oxidative stress and an accumulation of misfolded proteins in missed miscarriage placentas may contribute to the changes of senescence and endoplasmic reticulum stress seen in missed miscarriage placentas.

Keywords: endoplasmic reticulum stress; extracellular vesicles; miRNA sequence; miscarriage; misfolded proteins; placenta; senescence.