Group leader: 

Clare Blackburn

Position: 

Professor of Tissue Stem Cell Biology

Contact: 

c [dot] blackburn [at] ed [dot] ac [dot] uk

Aims
We study the mechanisms through which the thymus develops and is maintained, with a long-term view to developing therapeutic approaches for boosting immune system function.  In particular, we are focussed on the cellular and molecular regulation of thymic epithelial progenitor/stem cells.

Background
The thymus is one of the central organs of the immune system, as it is the major site of T cell generation and is therefore necessary for the development of the adaptive immune system.  The specialist functions required to support T cell development are provided largely by an array of functionally distinct epithelial cells that form a key part of the thymic stroma.  Notably, the thymus is one of the first organs to degenerate (or involute) in normal healthy individuals.  This has a number of consequences for immune system function, including increased susceptibility to infection and decreased response to vaccines with age.  Because of this, there is currently interest in developing strategies to boost thymus function by either cell replacement or regenerative strategies.    

This lab originally identified and functionally characterised the population of fetal tissue stem/progenitor cells from which the thymus arises during development, and demonstrated that this population can also establish a properly organized, fully functional thymus upon ectopic transplantation.  These thymic epithelial progenitor/stem cells may be useful in cell replacement therapies aimed at boosting adaptive immunity by increasing thymic output (for instance in athymic individuals, bone marrow or solid organ transplants, aging, and possibly HIV).  Our work addresses aspects of TEPC biology in mouse and human, and the cellular and molecular mechanisms that operate to maintain the postnatal organ.  Currently we are focussed on:

• transcription factor networks and specific genes that regulate specification and progression of the thymic epithelial lineage,
• thymic epithelial progenitor cell biology and regulation, including single cell analysis of potency and establishment of conditions for ex vivo propagation,
• differentiation of pluripotent cells into thymic epithelial progenitors,
• lineage relationships in the postnatal thymus,
• characterization of human thymus development.

Approaches and progress
We use population level and single cell approaches in vitro and in vivo, including reaggregate organ culture, in conjunction with genetic, biochemical and ‘omics approaches to investigate thymus development, maintainance and regeneration.

E11.5 pharyngeal arch region stained with anti-Cytokeratin (Green) to show epithelial cells, MTS24 (Red) and TO-PRO-3 (Blue) to reveal nuclei. MTS24 stains the common thymus-parathyroid primordium.

Selected publications

• Bonfanti P, Claudinot S, Amici AW, Farley A, Blackburn CC, Barrandon Y. 2010. Microenvironmental reprogramming of thymic epithelial cells to skin multipotent stem cells. Nature 466: 978-982. doi:10.1038/nature09269. Press release.
• Depreter MLG, Blair NF, Gaskell TL, Nowell CS, Davern K, Pagliocca A, Stenhouse F, Farley AM, Fraser A, Vrana J, Robertson K, Morahan G, Tomlinon SR, Blackburn CC. 2008. Identification of Plet1 as a specific marker of thymic epithelial progenitor cells.  Proc Natl Acad Sci USA 105:961-966.
• Gordon J, Wilson V, Blair NF, Sheridan J, Farley A, Wilson L, Manley NR, Blackburn CC. 2004. Functional evidence for a single origin for the thymic epithelium. Nat Immunol. Vol. 5: 546-553.
• Blackburn CC and Manley NR. 2004 Developing a new paradigm for thymus organogenesis. Nat Rev Immunol 4:278-289.
• Bennett AR, Farley A, Blair NF, Gordon J, Sharp L, Blackburn CC. 2002. Identification and characterization of thymic epithelial progenitor cells. Immunity 16:803-814.

Funding
Our research is supported by Leukaemia and Lymphoma Research, the European Union and the Medical Research Council.  We are currently participating in two EU FP7-funded stem cell projects EuroSyStem and OptiStem.