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Title: In vitro model to study the role of Notch pathway in the interaction between haematopietic stem cells (HSCs) and their microenvironment
Author: Audia, A. A.
ISNI:       0000 0004 5364 933X
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2015
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The very well conserved Notch pathway is known to be important in many aspects of haematopoiesis. The Notch ligands are expressed in the stromal bone marrow microenvironment and interact with Notch receptors expressed on the haematopoietic stem cells (HSCs) in order to maintain their immature and quiescent phenotype. The cell autonomous role of the Notch pathway has been recently elucidated in human HSCs maintenance. However little is known about the non-cell autonomous role played by the Notch pathway in the stromal microenvironment. The long-term culture (LTC) assay has been used as a model to study the interaction mediated by the Notch pathway between the HSCs and the MS-5 stromal cell line. In this study, for the first time, is shown that the HSPCs activate the Notch pathway in the MS-5 stromal cells through Notch2 receptor. The activation of the pathway induces an increase in the expression of Notch ligands Jag1, Jag2 and Delta4 and of Notch2 receptor in the stromal cells. Thus, enhancing in a positive feed-back loop the activation of the Notch pathway in the HSPCs and in the MS-5 cells. These data suggest that a cross-talk mediated by the Notch pathway is happening between the HSPCs and the stromal cells. Interestingly, in absence of Notch activation in the stroma, the HSPCs are pushed to proliferate and differentiate loosing their LTC-IC and in vivo engraftment potentials after co-culture. However, the inhibition of the cross-talk mediated by Notch inhibitors (GSIs) trigger a stronger phenotype, confirming the cell autonomous role played by Notch in HSPCs maintenance ex vivo. As shown in this study, the blockage of Jag1 ligand on the stroma culminates in a premature exhaustion of the HSPCs in culture due to proliferative stress. Differently, blocking Jag2 ligand on the stroma, HSPCs differentiate more and loose their engraftment potential after LTC. These results confirm the unique and exclusive role of the Notch ligands in the maintenance of the HSPCs ex vivo. Also, the Jag2 appears to be involved in the activation of the Notch pathway in MS-5 stroma, indicating a potential role in the maintenance of the MS-5 cells properties as well.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available