Functional Characterization of Syncytin Genes in Human Placental Development using iPSC-derived Trophoblast Models

Document Type

Article

Publication Date

2026

JAX Location

JGM

Abstract

Successful placental development depends on the differentiation and fusion of trophoblast cells into multinucleated syncytial structures. Following blastocyst implantation, trophectoderm cells fuse to first form the primitive syncytium (PrSyn), a transient multinucleated layer that facilitates embryo invasion and implantation

Cell fusion during these early stages is mediated by endogenous retroviral envelope proteins known as syncytins, including Syncytin-1 (ERVW-1) and Syncytin-2 (ERVFRD-1). While both proteins are established mediators of trophoblast fusion, their specific roles during PrSyn formation remain unclear. Env-p(B), another endogenous retroviral envelope protein found within the human genome and determined to be both fusogenic and immunosuppressive in cell-based assays, has not yet been functionally characterized in the trophoblast lineage. We had earlier identified Env-p(B) to be specifically expressed in the PrSyn (i.e. late-stage human blastocyst and PrSyn cell model) thus our interest in functionally characterizing it here. We gave Env-p(B) the tentative name of Syncytin-3. Understanding how these genes regulate PrSyn formation is essential for defining the mechanisms underlying normal placental development and pregnancy success.

To determine the role of these syncytins, we knocked out Syncytin-1, Syncytin-2, and Syncytin-3 in induced pluripotent stem cells (iPSCs) and differentiated them into PrSyn through a well-established protocol. Expression of marker genes of PrSyn were measured by RT-qPCR and immunofluorescence. We found that syncytin-1,2 loss reduced these markers expression, while syncytin-3 loss increased their expression and upregulated the expression of the two other syncytins. This may suggest syncytin-1,2 drive fusion while syncytin-3 regulates progression through the primitive syncytium stage.

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