胰岛素样生长因子（IGF）和成纤维细胞生长因子（FGF）在体外协同建立多能人类细胞的调节性干细胞生态位。

IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro.

作者信息

Bendall Sean C, Stewart Morag H, Menendez Pablo, George Dustin, Vijayaragavan Kausalia, Werbowetski-Ogilvie Tamra, Ramos-Mejia Veronica, Rouleau Anne, Yang Jiabi, Bossé Marc, Lajoie Gilles, Bhatia Mickie

机构信息

McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, and Department of Biochemistry, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.

出版信息

Nature. 2007 Aug 30;448(7157):1015-21. doi: 10.1038/nature06027. Epub 2007 Jul 11.

DOI:10.1038/nature06027

PMID:17625568

Abstract

Distinctive properties of stem cells are not autonomously achieved, and recent evidence points to a level of external control from the microenvironment. Here, we demonstrate that self-renewal and pluripotent properties of human embryonic stem (ES) cells depend on a dynamic interplay between human ES cells and autologously derived human ES cell fibroblast-like cells (hdFs). Human ES cells and hdFs are uniquely defined by insulin-like growth factor (IGF)- and fibroblast growth factor (FGF)-dependence. IGF 1 receptor (IGF1R) expression was exclusive to the human ES cells, whereas FGF receptor 1 (FGFR1) expression was restricted to surrounding hdFs. Blocking the IGF-II/IGF1R pathway reduced survival and clonogenicity of human ES cells, whereas inhibition of the FGF pathway indirectly caused differentiation. IGF-II is expressed by hdFs in response to FGF, and alone was sufficient in maintaining human ES cell cultures. Our study demonstrates a direct role of the IGF-II/IGF1R axis on human ES cell physiology and establishes that hdFs produced by human ES cells themselves define the stem cell niche of pluripotent human stem cells.

摘要

干细胞的独特特性并非自主实现，近期证据表明存在来自微环境的外部控制水平。在此，我们证明人类胚胎干细胞（ES细胞）的自我更新和多能特性取决于人类ES细胞与自体来源的人类ES细胞成纤维样细胞（hdFs）之间的动态相互作用。人类ES细胞和hdFs由胰岛素样生长因子（IGF）和成纤维细胞生长因子（FGF）依赖性独特定义。IGF 1受体（IGF1R）表达仅见于人类ES细胞，而FGF受体1（FGFR1）表达局限于周围的hdFs。阻断IGF-II/IGF1R途径会降低人类ES细胞的存活率和克隆形成能力，而抑制FGF途径会间接导致分化。hdFs在FGF刺激下表达IGF-II，单独的IGF-II就足以维持人类ES细胞培养。我们的研究证明了IGF-II/IGF1R轴对人类ES细胞生理学的直接作用，并确定人类ES细胞自身产生的hdFs定义了多能人类干细胞的干细胞龛。