About the Project
T cells are vital regulators and effectors of the adaptive immune system. Production of a functional, self-tolerant T cell development is a complex process that occurs in a dedicated organ, the thymus, and depends on a set of highly specialized epithelial cells that form a key part of the thymic stroma (thymic epithelial cells; TEC)(1). Two main sub-lineages of TEC exist: cortical and medullary TEC. These develop from a common progenitor/stem cell during thymus development, and are functionally distinct, regulating early T cell differentiation and central tolerance induction respectively.
In previous work, we identified the thymic epithelial progenitor/stem cells (TEPC) from which the TEC lineage first arises (2) and showed these cells can form self-organised thymic organoids in vitro (unpublished) and upon transplantation (2). Recently, we have also established that TEC can be generated in vitro by direct reprogramming of primary embryonic fibroblasts using a single transcription factor, FOXN1 (3). Like ex vivo TEPC, these ‘induced TEC’ (iTEC) can generate a thymus upon transplantation and form thymic organoids in vitro (3). Additionally, we have recently uncovered part of the mechanism controlling the very earliest development of the medullary TEC sublineage, which regulates central tolerance induction (4). We now wish to use the lineage tracing approaches, including barcoding, to (i) map the lineage relationships during the very earliest stages of TEC development and (ii) investigate iTEC generation of thymic organoids.
This interdisciplinary project is based at the interface of stem cell and developmental biology, and mathematical modelling. It will use a combination of bioinformatics, modelling and wet-lab approaches, including lineage tracing, barcoding and organoid technology, to identify lineage relationships in early TEC differentiation, and probe how these relate to iTEC-based thymic organoid formation.
The successful student will receive training in stem cell biology, bioinformatics analysis of single cell and population RNA-seq data, CAS9/CRISPR mediated genetic modification, tissue culture including of pluripotent stem cells, microdissection, cellular reaggregation techniques, thymic organoid culture, multiparameter FACS analysis, advanced imaging analysis, immunohistochemistry, RT-qPCR.
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(2) Bennett, A.R., Farley, A., Blair, N.F., Gordon, J., Sharp. L., and Blackburn, C.C.; (2002) Identification and characterization of thymic epithelial progenitor cells. Immunity 16 803-814
(3) Bredenkamp, N., Ulyanchenko, S., O’Neill, K.E., Manley, N.R., Vaidya, H.J. and Blackburn, C.C. (2014) An organized and functional thymus generated from FOXN1-reprogrammed fibroblasts. Nature Cell Biology, 16 902-8.
(4) Liu, D., Kousa, A.I., O’Neill, K.E., Rouse, P., Popis, M., Farley, A.M., Tomlinson, S.R., Ulyanchenko, S., Guillemot, F., Seymour, P.A., Jørgensen, M.C., Serup, P., Koch, U., Radtke, F., and Blackburn, C.C. (2020) Canonical Notch signaling controls the early thymic epithelial progenitor cell state and emergence of the medullary epithelial lineage in fetal thymus development. Development 147:dev178582. doi: 10.1242/dev.178582. PMID: 32467237
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