Resolving placenta accreta spectrum biology with spatial transcriptomics

Abstract

Placental accreta spectrum (PAS) is associated with severe obstetric morbidity. The pathophysiology involves myometrial invasion as a function of signaling between an abnormal decidual environment and uterine scar dehiscence. The cellular heterogeneity at the site of invasion and the function of cell types at the maternal-fetal interface have not been well characterized. Single-cell spatial transcriptomics allows cellular architecture to be maintained while understanding the cellular heterogeneity, serving as a tool for biomarker discover and more so, understanding PAS disease mechanism. We performed spatial transcriptomics and single-cell RNAseq assays to determine local gene expression profiles at the site of accreta invasion (AI) and a non-invasive site from the same placenta (AO), as well as in controls (C). We utilized the GeoMX Digital Spatial Profiler for RNA library preparation and sequencing for next-generational sequencing. We selected 12 regions of interest (ROI) per condition for spatial transcriptomic analysis. ROIs were compared following segmentation and probe QC. Spatial transcriptomics annotation identified distinct gene signature by condition – AI, AO, and C. Clustering analysis identified 99 genes differently regulated between AI versus AO. AI showed a unique gene signature most prominent in the endothelial and stromal cell populations. The highest expression in AI compared to AO and C was seen in the following genes: HGF, LAMA2, DCN, SPARC, COL3A1, EGFL6 and decreased in ANK1, PTX1 and MGARP. Gene set enrichment analysis identified the following key pathways: blood vessel development, regulation of cell adhesion and migration, and the integrin pathway. We present an in-depth transcriptomic characterization of PAS across the site of invasion and sites of non-adherence with relative morphological context. This high-resolution transcriptomic profiles with locality information of PAS helps to understanding disease mechanism and inform diagnostic and therapeutic discoveries, that currently imply loss of boundary limits on a cellular level.View Large Image Figure ViewerDownload Hi-res image Download (PPT)