Life Sciences Research for Lifelong Health

Myriam Hemberger

Myriam Hemberger is in the process of relocating to Canada to take up a Professorship at the University of Calgary. Her new webpage can be found here.

Research Summary

The focus of our work is on the establishment, maintenance and differentiation of trophoblast cells leading to formation of a functional placenta. The placenta is the defining organ of most mammals, providing a nutritive conduit that is crucial for all embryonic development to occur. Trophoblast cells are the major building blocks of the developing placenta. They are the first cell type to arise very early in development when they are set apart from cells giving rise to the embryo itself. The various functions of trophoblast cells early in development are vital for reproductive success, as they lay the foundations for a normal pregnancy and healthy foetus later on. A better understanding of the mechanisms underlying these early events will be critical to develop better screens and therapeutic avenues for pregnancy complications.
 
We are in particular interested in how the early trophoblast niche is regulated by transcription factors and specific epigenetic modifiers to ensure normal development. Leading on from this, we also investigate how susceptible the trophoblast compartment is to perturbations by extrinsic factors that activate specific signalling cascades, including in the context of development in mothers of advanced age. For this we are taking a range of high-throughput epigenomic and transcriptomic approaches to study these early events in placental development.
 
Key among our tools is the use of murine trophoblast stem (TS) cells, which mimic many of the properties of the early placenta. Learning about the self-renewal mechanisms of TS cells, in comparison to embryonic stem (ES) cells, will help us uncover the fundamental principles of how the early placenta develops and is influenced by external factors, which may be predictive for life long physiology and health. These insights will also enable us to better understand the earliest steps in human placentation and to develop novel cellular research tools to study the underlying molecular processes.

Latest Publications

Trophoblast organoids as a model for maternal-fetal interactions during human placentation.
Turco MY, Gardner L, Kay RG, Hamilton RS, Prater M, Hollinshead MS, McWhinnie A, Esposito L, Fernando R, Skelton H, Reimann F, Gribble FM, Sharkey A, Marsh SGE, O'Rahilly S, Hemberger M, Burton GJ, Moffett A

The placenta is the extraembryonic organ that supports the fetus during intrauterine life. Although placental dysfunction results in major disorders of pregnancy with immediate and lifelong consequences for the mother and child, our knowledge of the human placenta is limited owing to a lack of functional experimental models. After implantation, the trophectoderm of the blastocyst rapidly proliferates and generates the trophoblast, the unique cell type of the placenta. In vivo, proliferative villous cytotrophoblast cells differentiate into two main sub-populations: syncytiotrophoblast, the multinucleated epithelium of the villi responsible for nutrient exchange and hormone production, and extravillous trophoblast cells, which anchor the placenta to the maternal decidua and transform the maternal spiral arteries. Here we describe the generation of long-term, genetically stable organoid cultures of trophoblast that can differentiate into both syncytiotrophoblast and extravillous trophoblast. We used human leukocyte antigen (HLA) typing to confirm that the organoids were derived from the fetus, and verified their identities against four trophoblast-specific criteria. The cultures organize into villous-like structures, and we detected the secretion of placental-specific peptides and hormones, including human chorionic gonadotropin (hCG), growth differentiation factor 15 (GDF15) and pregnancy-specific glycoprotein (PSG) by mass spectrometry. The organoids also differentiate into HLA-G extravillous trophoblast cells, which vigorously invade in three-dimensional cultures. Analysis of the methylome reveals that the organoids closely resemble normal first trimester placentas. This organoid model will be transformative for studying human placental development and for investigating trophoblast interactions with the local and systemic maternal environment.

+ View Abstract

Nature, , 1476-4687, , 2018

PMID: 30487605

Regulation of Placental Development and Its Impact on Fetal Growth-New Insights From Mouse Models.
Woods L, Perez-Garcia V, Hemberger M

The placenta is the chief regulator of nutrient supply to the growing embryo during gestation. As such, adequate placental function is instrumental for developmental progression throughout intrauterine development. One of the most common complications during pregnancy is insufficient growth of the fetus, a problem termed intrauterine growth restriction (IUGR) that is most frequently rooted in a malfunctional placenta. Together with conventional gene targeting approaches, recent advances in screening mouse mutants for placental defects, combined with the ability to rapidly induce mutations and by CRISPR-Cas9 technology, has provided new insights into the contribution of the genome to normal placental development. Most importantly, these data have demonstrated that far more genes are required for normal placentation than previously appreciated. Here, we provide a summary of common types of placental defects in established mouse mutants, which will help us gain a better understanding of the genes impacting on human placentation. Based on a recent mouse mutant screen, we then provide examples on how these data can be mined to identify novel molecular hubs that may be critical for placental development. Given the close association between placental defects and abnormal cardiovascular and brain development, these functional nodes may also shed light onto the etiology of birth defects that co-occur with placental malformations. Taken together, recent insights into the regulation of mouse placental development have opened up new avenues for research that will promote the study of human pregnancy conditions, notably those based on defects in placentation that underlie the most common pregnancy pathologies such as IUGR and pre-eclampsia.

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Frontiers in endocrinology, 9, 1664-2392, 570, 2018

PMID: 30319550

Divergent wiring of repressive and active chromatin interactions between mouse embryonic and trophoblast lineages.
Schoenfelder S, Mifsud B, Senner CE, Todd CD, Chrysanthou S, Darbo E, Hemberger M, Branco MR

The establishment of the embryonic and trophoblast lineages is a developmental decision underpinned by dramatic differences in the epigenetic landscape of the two compartments. However, it remains unknown how epigenetic information and transcription factor networks map to the 3D arrangement of the genome, which in turn may mediate transcriptional divergence between the two cell lineages. Here, we perform promoter capture Hi-C experiments in mouse trophoblast (TSC) and embryonic (ESC) stem cells to understand how chromatin conformation relates to cell-specific transcriptional programmes. We find that key TSC genes that are kept repressed in ESCs exhibit interactions between H3K27me3-marked regions in ESCs that depend on Polycomb repressive complex 1. Interactions that are prominent in TSCs are enriched for enhancer-gene contacts involving key TSC transcription factors, as well as TET1, which helps to maintain the expression of TSC-relevant genes. Our work shows that the first developmental cell fate decision results in distinct chromatin conformation patterns establishing lineage-specific contexts involving both repressive and active interactions.

+ View Abstract

Nature communications, 9, 2041-1723, 4189, 2018

PMID: 30305613

Group Members

Latest Publications

Regulation of Placental Development and Its Impact on Fetal Growth-New Insights From Mouse Models.

Woods L, Perez-Garcia V, Hemberger M

Frontiers in endocrinology
9 1664-2392:570 (2018)

PMID: 30319550

Divergent wiring of repressive and active chromatin interactions between mouse embryonic and trophoblast lineages.

Schoenfelder S, Mifsud B, Senner CE

Nature communications
9 2041-1723:4189 (2018)

PMID: 30305613

A Critical Role of TET1/2 Proteins in Cell-Cycle Progression of Trophoblast Stem Cells.

Chrysanthou S, Senner CE, Woods L

Stem cell reports
2213-6711: (2018)

PMID: 29576538

Integrin α2 marks a niche of trophoblast progenitor cells in first trimester human placenta

Lee CQE, Turco M, Gardner L

Development (Cambridge, England)
1477-9129: (2018)

PMID: 29540503

Placentation defects are highly prevalent in embryonic lethal mouse mutants.

Perez-Garcia V, Fineberg E, Wilson R

Nature
1476-4687: (2018)

PMID: 29539633

Decidualisation and placentation defects are a major cause of age-related reproductive decline.

Woods L, Perez-Garcia V, Kieckbusch J

Nature communications
8 2041-1723:352 (2017)

PMID: 28874785

Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium.

Turco MY, Gardner L, Hughes J

Nature cell biology
1476-4679: (2017)

PMID: 28394884

From the stem of the placental tree: trophoblast stem cells and their progeny.

Latos PA, Hemberger M

Development (Cambridge, England)
143 1477-9129:3650-3660 (2016)

PMID: 27802134

What Is Trophoblast? A Combination of Criteria Define Human First-Trimester Trophoblast.

Lee CQ, Gardner L, Turco M

Stem cell reports
6 2213-6711:257-72 (2016)

PMID: 26862703