We identified a critical and conserved regulator of invasive trophoblast lineage development, Achaete-Scute Family Basic Helix-Loop-Helix Transcription Factor 2 (ASCL2). We found that depletion of ASCL2 in human trophoblast stem (TS) cells inhibits EVT formation, and global depletion of ASCL2 in vivo impairs invasive trophoblast development and causes mid-gestation embryonic lethality in the rat. However, the molecular mechanisms by which ASCL2 directs invasive trophoblast lineage development are unknown. To follow up on our initial findings, we are applying a combination of genomic and molecular biology approaches to establish the regulatory hierarchies driving extravillous and syncytiotrophoblast cell lineage development.

Well characterized human trophoblast stem cell lines will be informative, physiologic models of placental development and function. Each cell line will expand the genetic diversity of available models and be linked to robust clinical data that can be utilized to elucidate basic mechanisms underlying trophoblast cell lineage development. Overall, these models provide a unique opportunity to identify differences in trophoblast cell lineage development that may underlie pregnancy complications arising from suboptimal placentation.

The developing placenta is a target for the effects of several chemical substances found in the environment. However, the mechanisms by which many of the identified substances impact placental development have yet to be investigated. The Varberg lab aims to characterize the mechanisms by which individual chemicals and chemical mixtures alter trophoblast function using human trophoblast stem cells as in vitro models.