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Article
Nature 448, 1015-1021 (30 August 2007) | doi:10.1038/nature06027; Received 24 April 2007; Accepted 18 June 2007; Published online 11 July 2007
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IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro
Sean C. Bendall1,2,3, Morag H. Stewart1,3, Pablo Menendez1,4, Dustin George2, Kausalia Vijayaragavan1, Tamra Werbowetski-Ogilvie1, Veronica Ramos-Mejia1, Anne Rouleau1, Jiabi Yang1, Marc Bossé1, Gilles Lajoie2 & Mickie Bhatia1
- McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, and Department of Biochemistry, McMaster University, Hamilton, Ontario L8N 3Z5, Canada
- Don Rix Protein Identification Facility, Department of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 5C1, Canada
- These authors contributed equally to this work.
- Present address: Spanish Stem Cell Bank-Andalucian Branch, Instituto de Investigaciones Biomedicas, Granada 18100, Spain.
Correspondence to: Mickie Bhatia1 Correspondence and requests for materials should be addressed to M.B. (Email: mbhatia@mcmaster.ca).
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.
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