IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro.
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.
Bendall
Sean C
SC
McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, and Department of Biochemistry, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
Stewart
Morag H
MH
Menendez
Pablo
P
George
Dustin
D
Vijayaragavan
Kausalia
K
Werbowetski-Ogilvie
Tamra
T
Ramos-Mejia
Veronica
V
Rouleau
Anne
A
Yang
Jiabi
J
Bossé
Marc
M
Lajoie
Gilles
G
Bhatia
Mickie
M
D018929:Cell Culture Techniques; D002460:Cell Line; D049109:Cell Proliferation; D017077:Culture Media, Conditioned / Q000737:chemistry; D005346:Fibroblast Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D020543:Proteome / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013002:Somatomedins / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology
D017077:Culture Media, Conditioned; D020543:Proteome; D013002:Somatomedins; D016212:Transforming Growth Factor beta; D005346:Fibroblast Growth Factors; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1