The role of NAMPT/SIRTs signaling in hematopoietic differentiation

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Inducible pluripotent stem (iPS) cells are reprogrammed somatic cells with embryonic stem (ES) cell-like characteristics produced by the introduction of specific transcription factors (Oct 3/4, Sox2, Klf4, with or without c-MYC) into partially or fully differentiated somatic cells (e.g. fibroblasts, CD34+ bone marrow hematopoietic cells, keratinocytes from plucked human hair). Investigations using the iPS cells model can help to elucidate the processes of lineage specification and differentiation of several hematopoietic lineages. We have recently reported that nicotinamide phosphoribosyltransferase (NAMPT)-NAD+-SIRT1 pathway played an important role in G-CSF-induced myeloid differentiation of CD34+ hematopoietic cells in vitro and in vivo. NAMPT is a rate-limiting enzyme, which converts Nicotinamide into NAD+ and activates NAD+-dependent protein deacetylases, Sirtuins. Sirtuins are well known as lysine deacetylases for histones and numerous transcription factors. Recent reports demonstrated the importance of SIRT1 in the maintenance of pluripotency and differentiation of ES and iPS cells. However, less is known about the role of NAMPT and sirtuins in the hematopoietic and myeloid differentiation of iPS cells. The aim of the project is to delineate the role of NAMPT-NAD+-Sirtuins pathway in vitro in the hematopoietic differentiation of human iPS cells including early-stage of hematopoiesis and myeloid cell differentiation processes and in vivo in zebrafish model.