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Human dendritic cell development from induced-pluripotent stem cells

Student thesis: Doctoral ThesisDoctor of Philosophy

Dendritic cells (DCs) are a myeloid cell type specialised in processing and presenting antigens to T cells and they represent essential mediators of innate and adaptive immunity. In humans, DCs represent a very rare population of cells (0.02-0.8 % of leukocytes in the blood) and this aspect limits the ability to study human DCs subsets and their potential application in cell therapy-based translational studies. In order to overcome these limitations and provide a reliable system to differentiate human DCs from an inexhaustible source of cells, this work aims to develop a new experimental system to generate DCs from induced pluripotent stem cells (iPSCs), both in in vitro and in vivo settings. In this regard, a culture system based on engineered mouse stromal cells was established to support human DC development through the induction of a definitive hematopoietic program in iPSC-derived hematopoietic progenitors. 
The differentiation of human DCs from cord blood-derived hematopoietic progenitors was achieved and the heterogeneity of in vitro generated CD1c+ cells was investigated. Moreover, the ability of Flt3L to influence the early stages of hemato-endothelial specification was unravelled. 
Ultimately, this approach will be applied to genetically modified iPSC using CRISPR/Cas9 system. Candidate genes were identified and targeted in iPSCs in order to assess their influence on i) manipulate subsets commitment through transcriptional networks perturbation (i.e. IRF8, IRF4, ID2) and ii) manipulate DCs immunogenicity by targeting immune checkpoints (i.e. PD-L1).
Original languageEnglish
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Supervisors/Advisors
Award date1 Mar 2018

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