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

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

What Is Trophoblast? A Combination of Criteria Define Human First-Trimester Trophoblast.
Lee CQ, Gardner L, Turco M, Zhao N, Murray MJ, Coleman N, Rossant J, Hemberger M, Moffett A

Controversy surrounds reports describing the derivation of human trophoblast cells from placentas and embryonic stem cells (ESC), partly due to the difficulty in identifying markers that define cells as belonging to the trophoblast lineage. We have selected criteria that are characteristic of primary first-trimester trophoblast: a set of protein markers, HLA class I profile, methylation of ELF5, and expression of microRNAs (miRNAs) from the chromosome 19 miRNA cluster (C19MC). We tested these criteria on cells previously reported to show some phenotypic characteristics of trophoblast: bone morphogenetic protein (BMP)-treated human ESC and 2102Ep, an embryonal carcinoma cell line. Both cell types only show some, but not all, of the four trophoblast criteria. Thus, BMP-treated human ESC have not fully differentiated to trophoblast. Our study identifies a robust panel, including both protein and non-protein-coding markers that, in combination, can be used to reliably define cells as characteristic of early trophoblast.

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Stem cell reports, 6, 2213-6711, 257-72, 2016

PMID: 26862703

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Latest Publications

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

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

The H19 induction triggers trophoblast lineage commitment in mouse ES cells.

H Fujimori, H Mukai, Y Murakami

Biochemical and biophysical research communications
436 2:313-8 (2013)

DOI: 10.1016/j.bbrc.2013.05.100

PMID: 23743205