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

In early placental development, progenitor cytotrophoblasts (CTB) differentiate along one of two cellular trajectories: the villous or extravillous pathways. CTB committed to the villous pathway fuse with neighboring CTB to form the outer multinucleated syncytiotrophoblast (SCT), whereas CTB committed to the extravillous pathway differentiate into invasive extravillous trophoblasts (EVT). Unfortunately, little is known about the processes controlling human CTB progenitor maintenance and differentiation. To address this, we established a single cell RNA sequencing (scRNA-seq) dataset from first trimester placentas to identify cell states important in trophoblast progenitor establishment, renewal and differentiation. Multiple distinct trophoblast states were identified, representing progenitor CTB, column CTB, SCT precursors and EVT. Lineage trajectory analysis identified a progenitor origin that was reproduced in human trophoblast stem cell organoids. Heightened expression of basal cell adhesion molecule (BCAM) defined this primitive state, where BCAM enrichment or gene silencing resulted in enhanced or diminished organoid growth, respectively. Together, this work describes at high-resolution trophoblast heterogeneity within the first trimester, resolves gene networks within human CTB progenitors and identifies BCAM as a primitive progenitor marker and possible regulator.