Ryk mediated non-canonical Wnt signaling in the hematopoietic stem cell
Povinelli, Benjamin J.
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Hematopoiesis is the process by which all new blood cells are produced. This process depends on balanced regulation of self-renewal and differentiation of the hematopoietic stem cell (HSC). To achieve this balance HSCs are maintained in a quiescent state through a complex network of molecular signaling mechanisms. Although much is known about the intrinsic regulation of HSC quiescence, the cell-extrinsic signaling pathways remains poorly understood in HSCs. The identification of the molecular mechanism that regulate HSC biology has the potential for substantially impacting the clinical use of stem cell transplantation and in the prevention of myeloablative side effects of standard ontological therapies. In this dissertation a role of the atypical related to receptor tyrosine kinase protein (Ryk), is identified in the HSC. We observed that Ryk functionally interacts with the non-canonical Wnt ligand Wnt5a to increase HSC quiescence and repopulating ability in ex vivo cultures. In addition to this we identify a novel molecular role for Wnt5a-Ryk signaling in the regulation of reactive oxygen species in the HSC. Finally, we find that these molecular mechanisms functionally protect HSCs from myeloablative stress, and thus may be manipulated for therapeutic benefit. The work presented here represents a new field of research for the regulation of HSC biological function.