Hematopoietic Stem Cell (HSC)-based therapies are becoming a great expectation for the cure of several disorders that require HSCs for treatment. However, the incapacity to generate and maintain fully potent transplantable HSCs in vitro is still nowadays one of the main limitations for their wide application in cellular therapies. The study of the molecular mechanisms underlying HSC ontogeny in embryos is thus of crucial importance in order to elucidate the genetic networks that control the emergence and expansion of these cells.
HSCs are first and possibly entirely formed in arterial-endothelium during embryonic life, a process dependent on Notch-signalling. However, the molecular events regulating these signals are mainly unknown.
Fringe-glycosyltransferases are Notch modifiers contributing to the differential response of Notch to distinct ligands. It is hypothesized that the cross-talk between Notch and its cognate ligands in the arterial endothelium compartment is primarily a consequence of Fringe-mediated modification and the driving-force towards endothelium-HSC transition.
This project aims the elucidation of the role Fringe as modulators of Notch-signalling towards specification of HSC identity at mid-gestation mouse embryos, an issue that has not been addressed so far. This work will be initiated with the identification of the Fringe involved on HSC emergence and with the study on how the modulation of their expression is correlated with Notch-ligand responsiveness and formation of hematopoietic precursors in vitro. The results obtained in this part of the project will be the basis of further in vivo experiments, using Fringe knock-in and knock-out animal models.
The execution of this proposal should provide relevant clues on important biological questions involving stemness and cell differentiation. Moreover, it will pave the way for the development of new and more robust strategies to produce and expand HSCs a crucial issue for regenerative medicine.
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