Whole genome miRNA profiling revealed miR-199a as potential placental pathogenesis of selective fetal growth restriction in monochorionic twin pregnancies

Meng Meng; Yvonne Kwun Yue Cheng; Ling Wu; Piya Chaemsaithong; Maran Bo Wah Leung; Stephen Siu Chung Chim; Daljit Singh Sahota; Wei Li; Liona Chiu Yee Poon; Chi Chiu Wang; Tak Yeung Leung

doi:10.1016/j.placenta.2020.02.002

Whole genome miRNA profiling revealed miR-199a as potential placental pathogenesis of selective fetal growth restriction in monochorionic twin pregnancies

Placenta. 2020 Mar:92:44-53. doi: 10.1016/j.placenta.2020.02.002. Epub 2020 Feb 6.

Authors

Affiliations

¹ Department of Obstetrics and Gynaecology, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong. Electronic address: mengmengmumu@gmail.com.
² Department of Obstetrics and Gynaecology, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong. Electronic address: yvonnecheng@cuhk.edu.hk.
³ Department of Obstetrics and Gynaecology, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong. Electronic address: linda_wu@cuhk.edu.hk.
⁴ Department of Obstetrics and Gynaecology, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong. Electronic address: piyachaemsaithong@cuhk.edu.hk.
⁵ Department of Obstetrics and Gynaecology, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong. Electronic address: maranleung@cuhk.edu.hk.
⁶ Department of Obstetrics and Gynaecology, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong. Electronic address: sschim@cuhk.edu.hk.
⁷ Department of Obstetrics and Gynaecology, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong. Electronic address: daljit@cuhk.edu.hk.
⁸ Department of Obstetrics and Gynaecology, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong. Electronic address: liwei@link.cuhk.edu.hk.
⁹ Department of Obstetrics and Gynaecology, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong. Electronic address: liona.poon@cuhk.edu.hk.
¹⁰ Department of Obstetrics and Gynaecology, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong; Reproduction and Development, Li Ka Shing Institute of Health Sciences, the Chinese University of Hong Kong, Shatin, Hong Kong; School of Biomedical Sciences, the Chinese University of Hong Kong, Shatin, Hong Kong. Electronic address: ccwang@cuhk.edu.hk.
¹¹ Department of Obstetrics and Gynaecology, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong. Electronic address: tyleung@cuhk.edu.hk.

PMID: 32063549
DOI: 10.1016/j.placenta.2020.02.002

Abstract

Introduction: Placental-related mechanism of fetal growth restriction (FGR) is still unknown. Here we aimed to profile whole-genome miRNA between selective FGR twin (sFGR-T) and normally larger co-twin (sL-T) in monochorionic (MC) twin pregnancies and to further investigate effect of the miRNA on placental pathogenesis, including angiogenesis and mitochondrial functions.

Methods: MC twin pregnancies with or without sFGR were recruited, and their placental miRNAs were profiled (n = 3 vs 5). Ratio of placental miRNAs in the sFGR twin pairs (sFGR-T/sL-T) were calculated and compared to that in the control twin pairs (cS-T/cL-T). Differentially expressed miRNAs and associated markers were validated qRT-PCR, immunohistochemistry staining (n = 8 vs 13) and electron microscopy (n = 3 vs 3).

Results: Placental miR-199a-5p was significantly upregulated in sFGR-T (p = 0.004), which was validated by qRT-PCR (1.03 vs 0.56; p = 0.020). Compared to control twin pairs, ratio of CD31-positive vessels and volume density of vessels in sFGR twin pairs was lower (0.65 vs 0.92 and 18.7% vs 36.3%; both p < 0.001), while that of cyclooxygenase 2 (COX2)-positive trophoblast cells was higher (3.50 vs 2.22; p = 0.001), indicating an impaired angiogenesis and oxidative stress in the sFGR placenta. In addition, ratio of mitochondrial DNA (mtDNA) mitochondrial encoded NADH dehydrogenase 1 (MTND1) copy numbers (2.10 vs 0.90; p = 0.013), H-score ratios of mitochondrial markers citrate synthase (CS) and cytochrome c oxidase subunit 4 isoform 1 (COX4, 0.53 vs 0.95, p < 0.001; 0.29 vs 1.06, p < 0.001) in trophoblast cells of sFGR twin pairs were also altered significantly and correlated with angiogenesis. Furthermore, ratio of mitochondrial numbers per trophoblasts (8.67 vs 18.67; p = 0.006) and percentage of swollen mitochondria (84.33 vs 11.33; p = 0.003) were converted significantly, indicating mitochondrial damage.

Discussion: Our results suggested miR-199a-5p may play a role in the placental angiogenesis, oxidative stress and mitochondrial damage and dysfunction as an underlying pathogenesis of sFGR.

Keywords: MC twins; Mitochondria; Oxidative stress; miR-199a-5p; sFGR.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Case-Control Studies
Female
Fetal Growth Retardation / etiology
Fetal Growth Retardation / metabolism*
Fetal Growth Retardation / pathology
Genome-Wide Association Study
Humans
MicroRNAs / metabolism*
Mitochondria / ultrastructure
Neovascularization, Physiologic
Oxidative Stress
Placenta / pathology
Pregnancy
Prospective Studies
Twins, Monozygotic
Young Adult

Substances

MicroRNAs
mirn199 microRNA, human