OVO-like 1 regulates progenitor cell fate in human trophoblast development

Abstract

Epithelial barrier integrity is dependent on progenitor cells that either divide to replenish themselves or differentiate into a specialized epithelium. This paradigm exists in human placenta, where cytotrophoblast cells either propagate or undergo a unique differentiation program: fusion into an overlying syncytiotrophoblast. Syncytiotrophoblast is the primary barrier regulating the exchange of nutrients and gases between maternal and fetal blood and is the principal site for synthesizing hormones vital for human pregnancy. How trophoblast cells regulate their differentiation into a syncytium is not well understood. In this study, we show that the transcription factor OVO-like 1 (OVOL1), a homolog of Drosophila ovo, regulates the transition from progenitor to differentiated trophoblast cells. OVOL1 is expressed in human placenta and was robustly induced following stimulation of trophoblast differentiation. Disruption of OVOL1 abrogated cytotrophoblast fusion and inhibited the expression of a broad set of genes required for trophoblast cell fusion and hormonogenesis. OVOL1 was required to suppress genes that maintain cytotrophoblast cells in a progenitor state, including MYC, ID1, TP63, and ASCL2, and bound specifically to regions upstream of each of these genes. Our results reveal an important function of OVOL1 as a regulator of trophoblast progenitor cell fate during human trophoblast development.epithelial barrier | placenta | trophoblast | OVO-like 1 | differentiation E pithelial cells turn over regularly and are reliant on a pool of cells that either replenish the reservoir of progenitor cells or differentiate into the specialized epithelium required for that tissue's function. An excellent paradigm of epithelial turnover exists in the human placenta, where mononuclear cytotrophoblast cells lining the inner portion of the chorionic villi comprise the progenitor cells of the placental epithelium. These cells either propagate to maintain an adequate reservoir of progenitor cells or undergo a differentiation program that results in fusion with an overlying syncytium (1). This syncytium, termed "syncytiotrophoblast," forms the principal epithelial barrier separating maternal and fetal blood. Syncytiotrophoblast plays a vital role in regulating nutrient, water, waste, and gas exchange between maternal and fetal circulations and produces various hormones vital for fetal development and the maintenance of human pregnancy (2). Because of its importance for fetal health and development, disruptions in syncytiotrophoblast formation or functionality can have devastating consequences for pregnancy (3-5).Syncytiotrophoblast has a limited lifespan and is shed into the maternal circulation throughout pregnancy (6, 7). Therefore, to maintain the integrity of the maternal-fetal exchange surface, syncytiotrophoblast is continually replenished by select populations of cytotrophoblast cells that forego self-renewal and instead fuse into the overlying syncytiotrophoblast. This feature, analogous to paradigms established in othe...

Human Endometrial Extracellular Vesicles Functionally Prepare Human Trophectoderm Model for Implantation: Understanding Bidirectional Maternal‐Embryo Communication

“…Trophectodermal differentiation is species specific, and for the human this has been transcriptionally staged as early, mid, and late, within a transcriptional atlas of the human pre‐implantation embryo . Indeed, several of these genes had been previously associated with trophoblast differentiation including CCR7, CYP19A1, DLX, ERVFRD‐1, GCM1, GREM2, MUC15, and OVOL1 . For all of these, translation into protein was shown in our analysis of trophoblast spheroid proteins upregulated by endometrial EVs.…”

Notch1 controls development of the extravillous trophoblast lineage in the human placenta

“…Descriptive analyses in first trimester tissues and trophoblast cell models have been performed to gain insights into the expression patterns and epigenetic profiles of some of these genes (37,40,48,49). However, few of them have been functionally examined by using choriocarcinoma cells as surrogate for human primary trophoblasts (28,50). To extend our present knowledge, we herein analyzed expression of key regulators in the two purified CTB progenitor subtypes and performed functional analyses in these cells.…”

Comparison of syncytiotrophoblast generated from human embryonic stem cells and from term placentas

“…A few other trophoblast signature genes were down-regulated during the differentiation process, among them OVOL1 and ERVFRD-1. The former is a key transcription factor regulating fusion of progenitor cytotrophoblast (26), whereas ERVFRD-1 (formerly called syncytin-2) has recently been proposed to be a more important facilitator of trophoblast fusion than ERVW-1 (syncytin-1) (27). Presumably once cell fusion had begun, these two genes became quickly down-regulated in PHTd.…”