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Assessment of the role of Neuropeptide Y in the regulation of hematopoietic stem cells

Ulum, Barı
Differentiation, self-renewal and quiescence of Hematopoietic stem cells (HSCs) is tightly regulated and the majority of the immature adult stem cells is quiescent. This protects the HSCs from the strain of constant cell division and depletion of the stem cell pool. The neurotransmitter Neuropeptide Y (NPY) is released from sympathetic nerves in the central or peripheral nervous system. Neuropeptide Y (NPY) is secreted in the bone marrow niche by MSCs and has been shown to indirectly affect HSC function. However, the direct effects of NPY on HSCs has never been assessed. In the framework of this thesis, we aimed to explore the effect of NPY on the regulation of HSCs by performing a detailed analysis of the effects of NPY on HSC cell cycling and gene expression. The NPY receptors Y1-Y5 were highly expressed on most HSCs and mature hematopoietic cell subsets. In culture, expression of Y1, Y2, Y4 and Y5 was shown to decrease in time, whereas a signficant increase in the expression of NPY-Y3 was observed. Doses of 300 nM NPY suppressed HSC proliferation in cell cultures, as confirmed by an increase of HSCs in G0 phase and an increase in the gene expression levels of FOXO3, DICER1, PCNA, SMARCA2 and PDK1, which all have been shown to play an important role in the regulation of cell proliferation and quiescence. These data provide an indication that NPY plays a direct effect on the regulation of HSC fate, by modulating cell proliferation and quiescence.