Lineage relationship analysis of lymphoid progenitor subsets in the bone marrow of naïve mice and during inflammation.
Doctoral thesis, UCL (University College London).
During haematopoiesis multipotent stem cells generate all cellular components of the blood including lymphocytes. Despite great progress in the isolation of lineage restricted progenitors, the exact precursor-product relationship of these subsets remains poorly understood. In particular the exact branch point of T- and B-cell development in the bone marrow has not been unequivocally mapped. The aim of my project was to investigate the developmental relationship of various progenitor subsets in normal mice and during an acute inflammation. In order to permanently identify all cells which emanated from early lymphoid compartments we generated a mouse model in which a Cre recombinase was inserted into the Rag1 locus and functional Cre activity would result in activation of an eYFP reporter. Expression of the reporter was found in all T- and B-cells and in a significant subset of NK-cells and dendritic cells. Furthermore this model allowed the prospective isolation of an ‘ELP analogue’ and two subsets of CLPs on the basis of their reporter expression. Functional analysis of these subsets in vivo demonstrated comparable developmental properties with slightly different kinetics. Furthermore, in vitro analysis of isolated progenitors established that reporter-positive CLPs were significantly more advanced in their commitment to the B-cell lineage. We extended our studies by investigating the impact of an acute systemic inflammation on the size and composition of early haemato-lymphoid subsets. Administration of LPS or heat-inactivated E. coli to mice in vivo resulted in a complete halt of bone marrow lymphopoiesis. In addition, a marked decrease in the number of myeloid progenitors accompanied by upregulation of Sca-1 on haematopoietic progenitors was observed. These inflammation-induced changes were found to be mainly caused by IFNγ and to a lesser extend by TNFα, thus identifying these cytokines as key mediators for the infection-induced regulation of haematopoiesis.
|Title:||Lineage relationship analysis of lymphoid progenitor subsets in the bone marrow of naïve mice and during inflammation|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Infection and Immunity (Division of)|
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