The role of NAMPT/SIRTs signaling in hematopoietic differentiation

可诱导多能干细胞(IPS)是通过将特定的转录因子(Oct3/4、Sox2、Klf4，带有或不带有c-myc)导入部分或完全分化的体细胞(如成纤维细胞、CD34+骨髓造血细胞、拔除的人头发中的角质形成细胞)而产生的具有胚胎干细胞样特征的重编程体细胞。使用iPS细胞模型的研究有助于阐明几种造血系的谱系指定和分化过程。我们最近报道了烟酰胺磷酸核糖基转移酶(NAMPT)-NAD+-SIRT1通路在G-CSF诱导CD34+造血细胞向髓系分化中起重要作用。NAMPT是一种限速酶，它将烟酰胺转化为NAD+，并激活NAD+依赖的蛋白脱乙酰酶sirtuins。Sirtuins是众所周知的组蛋白和多种转录因子的赖氨酸脱乙酰酶。最近的报道表明，SIRT1在维持ES和iPS细胞的多能性和分化方面具有重要作用。然而，NAMPT和sirtuins在iPS细胞的造血系和髓系分化中的作用知之甚少。本研究旨在探讨NAMPT-NAD+-sirtuins通路在人iPS细胞体外造血分化中的作用，包括早期造血和髓系细胞分化过程，以及在体内斑马鱼模型中的作用。

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.