Transcription factor networks in trophoblast stem cell self-renewal and differentiation

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

Stem cells are of high interest for biomedical research and regenerative medicine. We are particularly interested in stem cells that are programmed to contribute exclusively to the placenta (so-called trophoblast stem cells). Very little is known as to how these stem cells are maintained in the normal placenta and what triggers them to differentiate into specific placental cell types. This project investigates specific molecules that we have identified to potentially play a role in these processes. The questions addressed are key to (a) understanding the underlying basis of normal pregnancy to ensure healthy babies and mothers, and (b) developing a physiological cell culture model system in which effects on placental formation and function can be assessed in a meaningful manner. Our approaches have great relevance to stem cell biology, reprogramming, regenerative medicine, mammalian reproduction and developmental biology.
 
Description Stem cells hold great therapeutic promise due to their ability to form many different cell types. Yet, even the most potent stem cell types can differentiate either only into all cell types of the embryo and later adult (so-called embryonic stem (ES) cells), or into placental cell types (trophoblast stem (TS) cells). However, ES cells cannot form placental cell types and vice versa. Therefore, this stem cell system perfectly reflects the first cell fate decision in development in which placental and embryonic cells are set apart.
In this project, we have investigated the degree to which ES cells can be reprogrammed to adopt TS cell fate. The rationale of these approaches was that they teach us about the molecular pathways that underpin the first cell fate decision that is absolutely crucial for all development to proceed. We find that such a fate switch can be initiated, but that the resulting cells retain a memory of their ES origin. Our insights are very informative for early differentiation steps and for the broadening our understanding of the use of stem cell differentiation protocols.
The work increased research capacity by training the student involved in high-level scientific research techniques, project design, data interpretation, scientific writing and presentation skills, leading to the successful award of a PhD.
Exploitation Route Others will make use of the molecular signatures we have identified that define each stem cell type, and that are retained even upon their differentiation and hence leave behind a reliable footprint of cell type origin.
Skill development, and research capacity building, due to in-depth training and expertise gained by scientist. Higher degree obtained (PhD).
Sectors Healthcare

 
Description Stem cell research and insights into molecular signatures that define cell types of the early embryo
First Year Of Impact 2012
Sector Healthcare
Impact Types Societal

 
Description MRC DTP Supplement Award
Amount £7,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2014 
End 12/2014
 
Title Profiling of epigenetic reprogramming between ESCs, MEFs and TSCs 
Description DNA methylation profiles of various ESC->TSC reprogramming models, as well as MEF->TSC reprogramming. 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact Datasets are deposited in publicly accessible databases. Findings show that an epigenetic memory is retained when reprogramming from ECSs, but less so when MEFs are used as starting material. 
 
Description Epigenetic memory in ES-to-TS cell reprogramming 
Organisation Babraham Institute
Country United Kingdom 
Sector Private 
PI Contribution Collaboration with Dr Simon Cook on the impact of Ras-Raf-Erk signalling on ES cell reprogramming towards trophoblast. Designed overall project outline and performed experimental analyses.
Collaborator Contribution Provided plasmid constructs and antibody resources. Provided help and advice on specific Western blotting techniques. Provided ongoing scientific advice.
Impact Cambuli F., Murray A., Dean, W., Dudzinska D., Krueger F., Andrews S., Senner C.E., Cook S. J. and Hemberger M. (2014). Epigenetic memory of the first cell fate decision prevents complete ES cell reprogramming into trophoblast. Nat. Commun., 5: 5538.
Start Year 2012
 
Description AM, participation in International Society for Stem Cell Research Meeting, Vancouver, Canada 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact The PhD student who attended this conference was selected for poster presentation at this prestigious international meeting.

Widening of scientific horizon, valuable experience in presentation skills, scientific interaction, establishing links with the scientific community world-wide
Year(s) Of Engagement Activity 2014
 
Description Invited presentation, CTR Annual Trophoblast Meeting, Cambridge, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Experience in public talking for the student; student's abstract was selected for oral presentation from amongst ~ 100 submissions.

Exchange of data, stimulation of wider thinking, exposure to international leaders in the field.
Year(s) Of Engagement Activity 2014
 
Description Royal Society Partnering Award - CS + LW, NM, SC 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Successful application for Royal Society Partnering Award. Poster 6 selected 6th form students over the course of 1 week and conducted in-depth research project. Data analysis followed at the pupils' school directly.
Year(s) Of Engagement Activity 2016,2017
 
Description School's Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact provided basic explanation of early development and the importance of the placenta for growth of a baby; hands-on experience for students in staining and microscopic analysis of a mouse placenta

rose awareness of research activities and importance of basic research to understand common pregnancy-associated diseases
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010