The role of NAMPT/SIRTs signaling in hematopoietic differentiation

诱导性多能干细胞（iPS）是具有胚胎干（ES）细胞样特征的重编程体细胞，通过将特定转录因子（Oct 34、Sox 2、Klf 4，有或没有c-MYC）引入部分或完全分化的体细胞（例如成纤维细胞、CD 34+骨髓造血细胞、来自拔下的人头发的角质形成细胞）中产生。使用iPS细胞模型的研究可以帮助阐明几种造血谱系的谱系特化和分化过程。我们最近报道，烟酰胺磷酸核糖转移酶（NAMPT）-NAD +-SIRT 1通路在体外和体内G-CSF诱导的CD 34+造血细胞髓样分化中发挥重要作用。NAMPT是一种限速酶，可将烟酰胺转化为NAD+，并激活NAD+依赖性蛋白脱乙酰酶Sirtuins。Sirtuins是组蛋白和许多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中的重要性。然而，关于NAMPT和sirtuins在iPS细胞的造血和髓样分化中的作用知之甚少。本项目的目的是描述NAMPT-NAD +-Sirtuins通路在体外人iPS细胞的造血分化中的作用，包括造血和髓样细胞分化过程的早期阶段，以及在斑马鱼模型中的体内作用。

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.