Derivation of thymic epithelial progenitor cells from ES cells

Lead Research Organisation: University of Edinburgh
Department Name: Sch of Biological Sciences

Abstract

Cellular immune responses, which control infection, allergy and transplant rejection, are co-ordinated and effected by T-cells. T-cell development takes place only in the thymus and depends on several specialized cell-types, called thymic epithelial cells, that are found only in that organ. The thymus is very active in children and young adults, but stops functioning in older people. This leads to problems in people who lose their original T cells such as bone marrow and organ transplantation patients, whose T cells have to be killed before the transplant can be accepted, and HIV patients. These patients need to generate new T cells in order to fight infections. My laboratory has recently identified a type of cell in the mouse embryonic thymus that can grow into a fully functional thymus when transplanted to a different site in the body. These cells, called thymic epithelial progenitor cells , may be useful for restoring immune function in patients with low T cell levels, either by transplantation of thymic epithelial progenitor cells to boost thymus activity, or by providing a way to grow T-cells efficiently in the laboratory. This could for instance provide bone marrow or organ transplant patients with safe, laboratory-grown T-cells while their own T cells were still regenerating. At the moment, the only source of thymic epithelial progenitor cells is embryonic thymus tissue. This presents a major barrier to the use of these cells for therapeutic purposes. Embryonic stem cells (ES cells) are a type of cell that can be grown indefinitely in the laboratory but can also differentiate into all cell-types and tissues found in the body (more information on ES cells, and other stem cell types, can be found on our website, http://www.iscr.ed.ac.uk/stemcells.html). Recently, scientists have successfully used ES cells to generate other more mature cell types in the laboratory. The cell types generated so far include neural stem cells, which may be used to repair damaged nerves in the future, and blood cells. The aim of this work is to establish a method for generating thymic epithelial progenitor cells from ES cells. This method would allow large numbers of thymic epithelial progenitor cells to be generated in the laboratory for therapeutic use. The study of thymic epithelial progenitor cells will also contribute important information to studies on how stem or progenitor cells function in general.

Technical Summary

Restoration of immune competence after transplantation requires thymus-dependent reconstitution of the T cell compartment and is problematic due to thymic involution. Interest therefore exists in the potential for therapeutic enhancement of thymus activity and the possibility of large-scale in vitro generation of defined T cell populations. We have recently isolated progenitor cells from mid-gestation mouse embryonic thymi that are sufficient to generate a functional thymus on transplantation. This population is likely to correspond to a common thymic epithelial progenitor cell (TEPC), that can differentiate into all thymic epithelial cell-types. TEPC have predicted clinical uses for boosting thymus function in transplant patients and to provide a means of ?patching? transplantation protocols using in vitro generated customised human T cell repertoires. However, at present they can be obtained only from foetal tissue. This proposal aims to provide a scaleable source via the direct differentiation and selective amplification of TEPC from ES cell cultures, with the long term goal of generating human ES-TEPC for clinical use.

Publications

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Depreter MG (2008) Identification of Plet-1 as a specific marker of early thymic epithelial progenitor cells. in Proceedings of the National Academy of Sciences of the United States of America

 
Description BBSRC iCASE PhD studentship
Amount £100,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2015 
End 08/2019
 
Description EU FP7 Collaborative Project
Amount € 6,000,000 (EUR)
Funding ID 602587 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 10/2013 
End 09/2017
 
Description School of Biological Sciences Postgraduate Scholarship
Amount £84,000 (GBP)
Organisation University of Edinburgh 
Sector Academic/University
Country United Kingdom
Start 10/2008 
End 09/2011
 
Description School of Biological Sciences Postgraduate Scholarship
Amount £84,000 (GBP)
Organisation University of Edinburgh 
Sector Academic/University
Country United Kingdom
Start 10/2010 
End 09/2013
 
Title ES cell line Plet1CreERt2 
Description This is an ES cell line in which CreERt2 is knocked in to exon 1 of the mouse Plet1 locus, such that it replaces Plet1 expression (knockin-knockout). This ES cell line has also been used to generate a Plet1CreERt2 transgenic mouse line. The CreERt2 is not functional unfortunately, but the mouse line is a Plet1 null. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2013 
Provided To Others? Yes  
Impact N/A 
 
Title Foxn1G 
Description This is an ES cell line and corresponding mouse strain carrying a revertible hypomorphic allele of Foxn1, where a flowed GFP cassette is knocked in to the Foxn1 locus such that it severely disrupts Foxn1 transcription. 
Type Of Material Cell line 
Provided To Others? No  
Impact This allele will be useful for reporting Foxn1 activity in vivo and in vitro, while minimizing the differentiation promoting activity of Foxn1. 
 
Description Generation of human ES cell reporter lines for identification of thymic epithelial lineage cells. 
Organisation University of Edinburgh
Department MRC Centre for Regenerative Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We contribute expertise in thymic epithelial cell biology, thymus organogenesis and ES differentiation to definiteive endoderm
Collaborator Contribution My collaborator contributes expertise in gene targeting in human ES cells, and in vector design.
Impact Research materials.
Start Year 2010