Cell trajectory modeling identifies a primitive trophoblast state defined by BCAM enrichment

Abstract

The establishment and function of the human placenta is dependent on specialized cells called trophoblasts. Progenitor cytotrophoblasts (CTBs) differentiate along one of two cellular trajectories: the villous or extravillous pathways. CTBs committed to the villous pathway fuse with neighboring CTBs forming the outer multinucleated syncytiotrophoblast layer (SCT), while CTBs committed to the extravillous pathway develop into multi-layered cell columns that anchor the placenta to uterine tissue. At distal column sites, column CTBs differentiate into invasive extravillous trophoblasts (EVT) that facilitate uterine remodeling of spiral arteries and modulate the maternal immune response to fetal antigen. Unfortunately, little is known about the cellular and molecular processes controlling human trophoblast stem cell maintenance and differentiation into these critical trophoblast sub-lineages. To address this, our laboratory established a single cell RNA sequencing (scRNA-seq) dataset from first trimester placentas to identify molecular programs and cell states important in trophoblast progenitor establishment, renewal, and differentiation. Using this dataset, eight distinct trophoblast states were identified, representing progenitor cytotrophoblasts, intermediate column CTBs, syncytiotrophoblast progenitors, and terminally differentiated EVT. Lineage trajectory analysis identified a CTB origin that was reproduced in human trophoblast stem cell organoids. Heightened expression of basal cell adhesion molecule (BCAM) defined this primitive state, where CTBs selected for high levels of surface BCAM expression generated larger clonally-derived organoids than did CTB counterparts expressing lower levels of BCAM. Together, this work resolves complex gene networks within human trophoblast progenitor cells, and identifies BCAM as marker that defines an up-stream progenitor origin.

Human placental biology at single‐cell resolution: a contemporaneous review

“…In 2021, Shannon et al. analysed 7798 cells from healthy placental villi from seven pregnant women during the first trimester and an additional 6309 cells from trophoblast organoid cultures by scRNA‐seq 57 . By comparing results with the published Vento‐Tormo et al.…”