GW2580

总览

GW2580 是 cFMS 激酶的选择性抑制剂 (IC₅₀ = 0.03 μM)（Conway et al., 2008），可阻断其自身磷酸化集落刺激因子 (CSF-1 或 M-CSF) 的能力，而集落刺激因子可促进巨噬细胞的存活、增殖和分化。

分化
·证实 CSF-1 在促进小鼠造血干细胞髓系谱系偏向中的重要性（Mossadegh-Keller et al.）。
·证实 CSF-1 在小鼠和人类巨噬细胞集落及单核细胞扩增中的重要性(He et al.; Clanchy et al.; Conway et al., 2008; Conway et al., 2005)。
·抑制人破骨细胞培养物、大鼠颅盖骨和大鼠胎儿长骨（Conway et al., 2005），以及小鼠关节炎模型（Conway et al., 2008）中的骨质退化。

细胞类型
间充质干/祖细胞，髓系细胞，成骨细胞

种属
人，小鼠，非人灵长类，其它细胞系，大鼠

应用
分化

研究领域
疾病建模，干细胞生物学

CAS 编号
870483-87-7

化学式
C₂₀H₂₂N₄O₃

纯度
≥98%

通路
CSF-1

靶点
cFMS

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产品说明书及文档

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Document Type

Product Name

Catalog #

Lot #

Language

Document Type

Product Information Sheet

Product Name

GW2580

Catalog #

72474, 72472

Lot #

All

Language

English

Document Type

Safety Data Sheet

Product Name

GW2580

Catalog #

72474, 72472

Lot #

All

Language

English

相关材料与文献

M-CSF instructs myeloid lineage fate in single haematopoietic stem cells. Mossadegh-Keller N et al. Nature 2013 MAY

Abstract

Under stress conditions such as infection or inflammation the body rapidly needs to generate new blood cells that are adapted to the challenge. Haematopoietic cytokines are known to increase output of specific mature cells by affecting survival, expansion and differentiation of lineage-committed progenitors, but it has been debated whether long-term haematopoietic stem cells (HSCs) are susceptible to direct lineage-specifying effects of cytokines. Although genetic changes in transcription factor balance can sensitize HSCs to cytokine instruction, the initiation of HSC commitment is generally thought to be triggered by stochastic fluctuation in cell-intrinsic regulators such as lineage-specific transcription factors, leaving cytokines to ensure survival and proliferation of the progeny cells. Here we show that macrophage colony-stimulating factor (M-CSF, also called CSF1), a myeloid cytokine released during infection and inflammation, can directly induce the myeloid master regulator PU.1 and instruct myeloid cell-fate change in mouse HSCs, independently of selective survival or proliferation. Video imaging and single-cell gene expression analysis revealed that stimulation of highly purified HSCs with M-CSF in culture resulted in activation of the PU.1 promoter and an increased number of PU.1(+) cells with myeloid gene signature and differentiation potential. In vivo, high systemic levels of M-CSF directly stimulated M-CSF-receptor-dependent activation of endogenous PU.1 protein in single HSCs and induced a PU.1-dependent myeloid differentiation preference. Our data demonstrate that lineage-specific cytokines can act directly on HSCs in vitro and in vivo to instruct a change of cell identity. This fundamentally changes the current view of how HSCs respond to environmental challenge and implicates stress-induced cytokines as direct instructors of HSC fate.

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Endothelial cells provide an instructive niche for the differentiation and functional polarization of M2-like macrophages. He H et al. Blood 2012 OCT

Abstract

Endothelial cells and macrophages are known to engage in tight and specific interactions that contribute to the modulation of vascular function. Here we show that adult endothelial cells provide critical signals for the selective growth and differentiation of macrophages from several hematopoietic progenitors. The process features the formation of well-organized colonies that exhibit progressive differentiation from the center to the periphery and toward an M2-like phenotype, characterized by enhanced expression of Tie2 and CD206/Mrc1. These colonies are long-lived depending on the contact with the endothelium; removal of the endothelial monolayer results in rapid colony dissolution. We further found that Csf1 produced by the endothelium is critical for the expansion of the macrophage colonies and that blockade of Csf1 receptor impairs colony growth. Functional analyses indicate that these macrophages are capable of accelerating angiogenesis, promoting tumor growth, and effectively engaging in tight associations with endothelial cells in vivo. These findings uncover a critical role of endothelial cells in the induction of macrophage differentiation and their ability to promote further polarization toward a proangiogenic phenotype. This work also highlights some of the molecules underlying the M2-like differentiation, a process that is relevant to the progression of both developmental and pathologic angiogenesis.

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HUVEC co-culture and haematopoietic growth factors modulate human proliferative monocyte activity. Clanchy FIL and Hamilton JA Cytokine 2012 JUL

Abstract

Monocytes and macrophages are often claimed to have limited potential for proliferation in vivo and in vitro although a human monocyte subset with increased potential to proliferate in culture, termed the proliferative monocyte (PM), has previously been identified. The response of the putatively less mature PM to conditions conducive to haematopoietic stem cell culture was determined. Co-culture of monocytes on a HUVEC monolayer induced up to four cell divisions in a 9 day period. The PM response to haematopoietic growth factors (Flt3L, SCF, IL-6, IL-3 and M-CSF) was determined. M-CSF induced the greatest proliferative response in PM; IL-3 and Flt3L reduced basal and M-CSF-induced proliferation. The inhibition of M-CSFR kinase activity by GW2580 indicated that the ligand(s) for this receptor was a potent inducer of proliferation of this subset; inhibitors of intracellular signalling pathways also reduced PM proliferation.

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