Research by a team from the University of California might change how clinicians and scientists understand, diagnose and treat placenta accreta spectrum disorder, a serious condition in which the placenta fails to separate from the uterus at birth, jeopardising the life and health of both mother and baby.
Previously, it was believed that certain overly invasive placental cells, called trophoblasts, were responsible for keeping the connection intact, reports Newswise.
But the latest study, which identifies genetic and cellular changes within single cells where the placenta and uterus join, shifts the focus to how the structural support of tissues, and the blood vessels of the uterus, can cause a “loss of normal boundary limits” between the placenta and the uterus.
“We utilised two new techniques in single-cell analysis to create an atlas of cells involved in placenta accreta to better understand this increasingly prevalent disorder,” said Dr Yalda Afshar, a maternal-foetal medicine specialist and researcher at the David Geffen School of Medicine at UCLA, and the first and corresponding author of an article describing the findings in the American Journal of Obstetrics & Gynaecology.
“This work revealed a subset of genes differentially expressed in placenta accreta spectrum disorder, which provides the basis for the ‘permissive environment’ for the placenta to attach to the uterine lining,” said Dr Deborah Krakow, a maternal-foetal medicine specialist and researcher, chair of the Department of Obstetrics and Gynaecology at the David Geffen School of Medicine, and the paper’s senior author.
The research showed that the decidua, the layer of the uterine lining that forms during pregnancy, and blood vessels, are sending different signals to the placenta when a pregnant woman has placenta accreta.
Normally, the placenta is shed after birth. In placenta accreta, it is attached too tightly, the reason for many of the maternal complications of the condition.
“Our goal was to characterise the intimate relationship between the maternal and foetal tissue at the site of accreta or malfunction,” Afshar said. “The genes and signalling pathways we identified go beyond providing a better understanding of the mechanism of the disease; they may be used as targets to help us refine diagnostic tests, track disease progression over time, and discover new, more effective therapies.”
The incidence of placenta accreta spectrum (PAS) disorders has increased dramatically in recent decades, the cause of which is not certain, though a Caesarean delivery is one of several risk factors.
Today, incidence is estimated at one in 272 births in the US, up from one in about 30 000 pregnancies in the 1960s, researchers say.
For this study, the team performed multiple placental biopsies on 12 placentas – six with PAS disorder and six controls – conducting single-cell RNA analysis on 31 406 individual cells.
They also applied spatial transcriptomics to 36 regions of interest – 12 in PAS-adherent, 12 in PAS-nonadherent, and 12 in controls.
Spatial transcriptomics allow researchers to precisely measure and map the gene activity within a single tissue sample.
“Understanding the biology of pregnancy and pregnancy-related diseases, like accreta, is inspired by only one thing – finding ways to improve the care we can provide to pregnant women and their families,” said Afshar, a physician-scientist who manages the care of many patients with placenta accreta spectrum disorders at UCLA Health.
Study details
Placenta accreta spectrum disorder at single-cell resolution: a loss of boundary limits in the decidua and endothelium
Yalda Afshar, Ophelia Yin, Deborah Krakow, et al.
Published in AJOG on 25 February 2024
Background
Placenta accreta spectrum disorders are associated with severe maternal morbidity and mortality. Placenta accreta spectrum disorders involve excessive adherence of the placenta preventing separation at birth. Traditionally, this condition has been attributed to excessive trophoblast invasion; however, an alternative view is a fundamental defect in decidual biology.
Objective
This study aimed to gain insights into the understanding of placenta accreta spectrum disorder by using single-cell and spatially resolved transcriptomics to characterise cellular heterogeneity at the maternal-foetal interface in placenta accreta spectrum disorders.
Study Design
To assess cellular heterogeneity and the function of cell types, single-cell RNA sequencing and spatially resolved transcriptomics were used. A total of 12 placentas were included, 6 placentas with placenta accreta spectrum disorder and 6 controls. For each placenta with placenta accreta spectrum disorder, multiple biopsies were taken at the following sites: placenta accreta spectrum adherent and non-adherent sites in the same placenta. Of note, 2 platforms were used to generate libraries: the 10× Chromium and NanoString GeoMX Digital Spatial Profiler for single-cell and spatially resolved transcriptomes, respectively. Differential gene expression analysis was performed using a suite of bioinformatic tools (Seurat and GeoMxTools R packages). Correction for multiple testing was performed using Clipper. In situ hybridization was performed with RNAscope, and immunohistochemistry was used to assess protein expression.
Results
In creating a placenta accreta cell atlas, there were dramatic difference in the transcriptional profile by site of biopsy between placenta accreta spectrum and controls. Most of the differences were noted at the site of adherence; however, differences existed within the placenta between the adherent and nonadherent site of the same placenta in placenta accreta. Among all cell types, the endothelial-stromal populations exhibited the greatest difference in gene expression, driven by changes in collagen genes, namely collagen type III alpha 1 chain (COL3A1), growth factors, epidermal growth factor–like protein 6 (EGFL6), and hepatocyte growth factor (HGF), and angiogenesis-related genes, namely delta-like noncanonical Notch ligand 1 (DLK1) and platelet endothelial cell adhesion molecule-1 (PECAM1). Intraplacental tropism (adherent versus non-adherent sites in the same placenta) was driven by differences in endothelial-stromal cells with notable differences in bone morphogenic protein 5 (BMP5) and osteopontin (SPP1) in the adherent vs nonadherent site of placenta accreta spectrum.
Conclusion
Placenta accreta spectrum disorders were characterised at single-cell resolution to gain insight into the pathophysiology of the disease. An atlas of the placenta at single cell resolution in accreta allows for understanding in the biology of the intimate maternal and foetal interaction. The contributions of stromal and endothelial cells were demonstrated through alterations in the extracellular matrix, growth factors, and angiogenesis. Transcriptional and protein changes in the stroma of placenta accreta spectrum shift the etiologic explanation away from “invasive trophoblast” to “loss of boundary limits” in the decidua. Gene targets identified in this study may be used to refine diagnostic assays in early pregnancy, track disease progression over time, and inform therapeutic discoveries.
See more from MedicalBrief archives:
C-section literature review on long-term risks and benefits
C-sections carry much higher mortality risk in Africa
RNA molecules in maternal blood may predict pregnancies at risk for pre-eclampsia