Mechanisms of Activin/Nodal signalling in pluripotency and differentiation of human embryonic stem cells

Lead Research Organisation: University of Cambridge
Department Name: Surgery

Abstract

Stem cells are remarkable in having the capacity to undergo specialisation into distinct tissue types, such as blood or skin. In addition, many stem cells are capable of self-renewal during cell division, so that they not only generate a specialised cell but also generate another stem cell. Our bodies are thereby able to retain their tissue-specific stem cells (such as those responsible for generating blood or skin) for our entire lifetimes. Such adult stem cells are generally thought to generate only a few types of cells, related to the specific tissue that they are derived from and are responsible for maintaining. Another type of stem cell can be derived from early stages of human development, namely from surplus embryos that arise in the treatment of human infertility using in vitro fertilisation. Such spare embryos, donated under informed consent by patients who have completed their therapies, are capable of generating embryonic stem cells when grown in petri dish. These stem cells are particularly interesting because they appear to have the ability to specialise into all of the tissue types in the entire body.

The current proposal is to investigate the molecular details of how human embryonic stem cells maintain their pluripotency, and how the biochemical information that is responsible for starting their journey on the path to specialisation actually works.

Technical Summary

In order to achieve the therapeutic potential of human embryonic stem cells, it will be necessary to scale up their growth in pristine conditions, and to generate significant quantities of clinically useful cell types. These goals will require an understanding of the mechanisms of pluripotency and differentiation in these cells. Current information indicates that human embryonic stem cells differ from their mouse counterparts in this regard. We therefore propose to investigate how the growth factors Activin and Nodal and their Smad signalling pathway act first to maintain pluripotency and then to induce differentiation into the precursors of mesoderm and endoderm.

Our hypothesis is that a distinct set of Smad binding partners are involved in maintaining pluripotency, and our first objective is to identify and functionally evaluate them. We also propose studies of the forkhead transcription factor, FoxH1, to determine how it functions during mesoderm and endoderm differentiation. Our third objective is to identify the downstream target genes through which these Smad binding partners exert their effects. These studies should provide essential insights into how Activin, Nodal and related growth factors are able to have varied developmental roles and should reveal how they can be used to generate homogeneous populations of either pluripotent or differentiated human cells for therapeutic use.
 
Description BHF Studentship
Amount £103,878 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2010 
End 03/2013
 
Description Neuroscience collaboration 
Organisation University of Cambridge
Department Department of Physiology, Development and Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution We provided space and stem cell culture expertise for the collaboration.
Collaborator Contribution Provision of postdoctoral fellow for collaborative effort.
Impact See co-authored paper with Lupo and Harris. Multidisciplinary: Neuroscience and stem cells
Start Year 2007
 
Title Chemically defined differentiation 
Description We discovered methods for inducing the differentiation of pluripotent human stem cells into neural, mesoderm/endoderm, and extraembryonic tissues using feeder-free, serum-free conditions. 
IP Reference WO2008056166 
Protection Patent application published
Year Protection Granted 2008
Licensed No
Impact None
 
Title Pluripotent cells from the mammalian late epiblast layer 
Description This invention relates to the isolation and propagation of pluripotent cells isolated from the mammalian late epiblast layer, termed Epiblast Stem Cells' (EpiSCs). These cells are useful in a range of applications. 
IP Reference WO2008056173 
Protection Patent granted
Year Protection Granted 2008
Licensed No
Impact None to date
 
Title Populations of smooth muscle cells of specific embryonic lineages 
Description Sinha S, Cheung C, Bernardo A and Pedersen R. filed this application regarding a method for generating embryonic region type-specific smooth muscle cells from pluripotent stem cells in vitro. 
IP Reference WO2012172328 
Protection Patent application published
Year Protection Granted 2011
Licensed No
Impact None to date
 
Title Transcription factor mediated programming towards megakaryocytes 
Description Moreau T, Trotter MWB, Ouwehand W and Pedersen RA filed this application regarding a method for generating human megakaryocytes from human pluripotent stem cells using direct programming. 
IP Reference WO2013190296 
Protection Patent application published
Year Protection Granted 2012
Licensed No
Impact None to date
 
Company Name Definigen 
Description Research and experimental development on biotechnology 
Year Established 2011 
Impact Supplying chemically-defined medium and hepatocytes produced therefrom for drug discovery and toxicity testing.
Website http://www.definigen.com/