Life Sciences Research for Lifelong Health

Myriam Hemberger

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

Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium.
Turco MY, Gardner L, Hughes J, Cindrova-Davies T, Gomez MJ, Farrell L, Hollinshead M, Marsh SGE, Brosens JJ, Critchley HO, Simons BD, Hemberger M, Koo BK, Moffett A, Burton GJ

In humans, the endometrium, the uterine mucosal lining, undergoes dynamic changes throughout the menstrual cycle and pregnancy. Despite the importance of the endometrium as the site of implantation and nutritional support for the conceptus, there are no long-term culture systems that recapitulate endometrial function in vitro. We adapted conditions used to establish human adult stem-cell-derived organoid cultures to generate three-dimensional cultures of normal and decidualized human endometrium. These organoids expand long-term, are genetically stable and differentiate following treatment with reproductive hormones. Single cells from both endometrium and decidua can generate a fully functional organoid. Transcript analysis confirmed great similarity between organoids and the primary tissue of origin. On exposure to pregnancy signals, endometrial organoids develop characteristics of early pregnancy. We also derived organoids from malignant endometrium, and so provide a foundation to study common diseases, such as endometriosis and endometrial cancer, as well as the physiology of early gestation.

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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

Trophoblast stem cells (TSCs) retain the capacity to self-renew indefinitely and harbour the potential to differentiate into all trophoblast subtypes of the placenta. Recent studies have shown how signalling cascades integrate with transcription factor circuits to govern the fine balance between TSC self-renewal and differentiation. In addition, breakthroughs in reprogramming strategies have enabled the generation of TSCs from fibroblasts, opening up exciting new avenues that may allow the isolation of this stem cell type from other species, notably humans. Here, we review these recent advances in light of their importance for understanding placental pathologies and developing personalised medicine approaches for pregnancy complications.

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

PMID: 27802134

Plet1 is an epigenetically regulated cell surface protein that provides essential cues to direct trophoblast stem cell differentiation.
Murray A, Sienerth AR, Hemberger M

Gene loci that are hypermethylated and repressed in embryonic (ESCs) but hypomethylated and expressed in trophoblast (TSCs) stem cells are very rare and may have particularly important roles in early developmental cell fate decisions, as previously shown for Elf5. Here, we assessed another member of this small group of genes, Placenta Expressed Transcript 1 (Plet1), for its function in establishing trophoblast lineage identity and modulating trophoblast differentiation. We find that Plet1 is tightly repressed by DNA methylation in ESCs but expressed on the cell surface of TSCs and trophoblast giant cells. In hypomethylated ESCs that are prone to acquire some trophoblast characteristics, Plet1 is required to confer a trophoblast-specific gene expression pattern, including up-regulation of Elf5. Plet1 displays an unusual biphasic expression profile during TSC differentiation and thus may be pivotal in balancing trophoblast self-renewal and differentiation. Furthermore, overexpression and CRISPR/Cas9-mediated knockout in TSCs showed that high Plet1 levels favour differentiation towards the trophoblast giant cell lineage, whereas lack of Plet1 preferentially induces syncytiotrophoblast formation. Thus, the endogenous dynamics of Plet1 expression establish important patterning cues within the trophoblast compartment by promoting differentiation towards the syncytiotrophoblast or giant cell pathway in Plet1-low and Plet1-high cells, respectively.

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Scientific reports, 6, 2045-2322, 25112, 2016

PMID: 27121762

01223 496534

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Keywords

developmental biology
embryo
epigenetics
placenta
stem cells
trophoblast

Group Members

Latest Publications

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

Maternal DNA Methylation Regulates Early Trophoblast Development.

Branco MR, King M, Perez-Garcia V

Developmental cell
36 1878-1551:152-63 (2016)

PMID: 26812015

Direct Induction of Trophoblast Stem Cells from Murine Fibroblasts.

Kubaczka C, Senner CE, Cierlitza M

Cell stem cell
17 1875-9777:557-68 (2015)

PMID: 26412560

Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of trophoblast stem cells.

Latos PA, Goncalves A, Oxley D

Nature communications
6 2041-1723:7776 (2015)

PMID: 26206133

ADP-ribosyltransferases Parp1 and Parp7 safeguard pluripotency of ES cells.

Roper SJ, Chrysanthou S, Senner CE

Nucleic acids research
42 1362-4962:8914-27 (2014)

PMID: 25034692

Derivation and maintenance of murine trophoblast stem cells under defined conditions.

Kubaczka C,Senner C,Arauzo-Bravo MJ,Sharma N,Kuckenberg P,Becker A,Zimmer A,Brustle O,Peitz M, M Hemberger,Schorle H

Stem cell reports
2 2213-6711:232-42 (2014)

PMID: 24527396