IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro.
Bendall, Sean C. 1,2*; Stewart, Morag H. 1*; Menendez, Pablo 1+; George, Dustin 2; Vijayaragavan, Kausalia 1; Werbowetski-Ogilvie, Tamra 1; Ramos-Mejia, Veronica 1; Rouleau, Anne 1; Yang, Jiabi 1; Bosse, Marc 1; Lajoie, Gilles 2; Bhatia, Mickie 1
[Article] Nature. 448(7157):1015-1021, August 30, 2007.

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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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