Ward Ellen J, Shcherbata Halyna R, Reynolds Steven H, Fischer Karin A, Hatfield Steven D, Ruohola-Baker Hannele
Department of Biochemistry, Institute for Stem Cell and Regenerative Medicine, School of Medicine, Box 357350, 1959 NE Pacific Street, University of Washington, Seattle, Washington 98195, USA.
Curr Biol. 2006 Dec 5;16(23):2352-8. doi: 10.1016/j.cub.2006.10.022. Epub 2006 Nov 2.
Stem cells are maintained and retain their capacity to continue dividing because of the influence of a niche. Although niches are important to maintain "stemness" in a wide variety of tissues, control of these niches is poorly understood. The Drosophila germline stem cells (GSCs) reside in a somatic cell niche. We show that Notch activation can induce the expression of niche-cell markers even in an adult fly; overexpression of Delta in the germline, or activated Notch in the somatic cells, results in extra niche cells, up to 10-fold over the normal number. In turn, these ectopic niche cells induce ectopic GSCs. Conversely, when GCSs do not produce functional Notch ligands, Delta and Serrate, the TGF-beta pathway is not activated in the GSCs, and they differentiate and subsequently leave the niche. Importantly, clonal analysis reveals that the receiving end of the Notch pathway is required in the somatic cells. These data show that a feedback loop exists between the stem cells and niche cells. Demonstration that stem cells can contribute to niche function has far-reaching consequences for stem cell therapies and may provide insight into how cancer can spread throughout an organism via populations of cancer stem cells.
由于微环境的影响,干细胞得以维持并保留其持续分裂的能力。尽管微环境对于在多种组织中维持“干性”很重要,但对这些微环境的调控却知之甚少。果蝇生殖系干细胞(GSCs)存在于体细胞微环境中。我们发现,Notch激活即使在成年果蝇中也能诱导微环境细胞标志物的表达;生殖系中Delta的过表达,或体细胞中激活的Notch,会导致额外的微环境细胞,数量最多可比正常数量多10倍。反过来,这些异位的微环境细胞会诱导异位GSCs的产生。相反,当生殖系干细胞不产生功能性的Notch配体Delta和锯齿蛋白时,TGF-β信号通路在生殖系干细胞中不会被激活,它们会分化并随后离开微环境。重要的是,克隆分析表明,Notch信号通路的接收端在体细胞中是必需的。这些数据表明,干细胞和微环境细胞之间存在反馈回路。证明干细胞可以对微环境功能做出贡献,这对干细胞治疗具有深远影响,并可能为癌症如何通过癌症干细胞群体在整个生物体中扩散提供见解。