Myriam Hemberger

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Placental development underpinning fetal and maternal health

Genetic and epigenetic control of early cell lineage decisions that dictate stem cell potency and underlie formation of a functional placenta

The earliest differentiative decision after fertilization sets cells of the future placenta aside from those of all other tissues, including the embryo proper. These events dictate the developmental potency of stem cells derived from the early embryo, most notably embryonic and trophoblast stem cells.

Trophoblast tissues that form the later placenta mediate implantation and nutrition of the growing fetus during pregnancy, and this imminent importance is reflected by the early stage of their emergence. Formation of the placenta is tightly controlled by a variety of genes with major players including key transcription factors, epigenetic regulators, imprinted genes and proteases. Because placental function is essential for fetal growth and survival and is also implicated in the aetiology of important pathologies in later life such as cardiovascular diseases and diabetes, knowledge in this field is crucial to advance our understanding of the molecular mechanisms that ensure a successful pregnancy as well as healthy aging.

The focus of our research is how stem cell self-renewal and differentiation of the various placental cell types is controlled.  We have found that at early stages, a tight epigenetic barrier - established by DNA methylation of a critical transcription factor - sets cells with a trophoblast cell fate apart from those that will form the embryo proper. A trophoblast stem (TS) cell niche is established that is controlled by a transcription factor network akin to the situation in ES cells. Exit from this stem cell compartment leads to the onset of differentiation into specific trophoblast cell types.

One of these, termed trophoblast giant cell, can invade into the uterus and interact with maternal arteries where these cells induce an amazing physiological remodeling process of the maternal vasculature. We are investigating genes that regulate trophoblast differentiation and invasion into the uterus, and how they affect supply of maternal blood to the placenta. Complementing this genetic control, we are also studying the epigenetic mechanisms that help maintain trophoblast specific gene expression patterns.

Our approaches are aimed to provide important insights into the genetic–epigenetic interplay that underlies these fundamental processes to ensure normal embryonic development, healthy babies and mothers as well as health during adult life.