Spatial multiomic landscape of the human placenta at molecular resolution

Successful pregnancy and healthy human embryo development rely directly on the placenta’s complex, dynamic gene regulatory networks, both within placental subtypes and at the maternal-fetal interface (MFI), that underlie stemness, proliferation, differentiation, invasion, immune tolerance, and communication. These cellular and molecular mechanisms are notoriously challenging to elucidate and make this organ arguably the least understood in the human body. Additionally, disruption of this vast collection of intercellular and intracellular programs and pathways leads to pregnancy complications and developmental defects. Here, we generated a comprehensive spatially resolved multi-modal cell census elucidating the molecular architecture of the first trimester human placenta. We utilized paired single-cell ATAC and RNA sequencing, spatial single-cell ATAC and RNA sequencing (Slide-tags), and in situ sequencing and hybridization mapping of transcriptomes at molecular resolution (STARmap-ISS and STARmap-ISH) using 922,961 cells to construct a spatial single-cell atlas outlining joint epigenomic and transcriptomic regulatory dynamics. Paired analyses unraveled intricate tumor-like gene expression and transcription factor motif programs sustaining the placenta in a hostile uterine environment; further investigation of gene-linked cis-regulatory elements revealed heightened regulatory complexity governing trophoblast differentiation and placental disease risk. Complementary spatial mapping techniques decoded these programs within the placental villous core and extravillous trophoblast (EVT) cell column architecture while simultaneously revealing niche-establishing transcriptional elements and cell-cell communication. To unify our datasets, we computationally imputed 33,357-gene multiomic single-cell profiles and spatially characterized the placental chromatin accessibility landscape. This spatially resolved single-cell multiomic framework of the first trimester human placenta at molecular resolution serves as a blueprint for future studies investigating cellular and molecular programs regulating early placental development and pregnancy.