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

Nature volume 448, pages 1015–1021 (2007)Cite this article

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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Figure 1: Receptor expression reveals human ES cell heterogeneity.
Figure 2: Immunocytochemistry staining of undifferentiated human ES cell cultures.
Figure 3: Differential IGF and FGF effects on human ES cells.
Figure 4: Function of IGF and its production in human ES cell cultures.
Figure 5: FGF-induced TGF-β signals required for human ES cell pluripotency.
Figure 6: Proposed model of human ES cell paracrine regulation.

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Acknowledgements

S.C.B. is supported by a CIHR Canada Graduate Scholarship doctoral award; M.H.S. by a postgraduate scholarship award from the Stem Cell Network and CIHR Canada Graduate Scholarship doctoral award; and M.Bh. by the Canadian Chair Program who holds the Canada Research Chair in human stem cell biology and Michael G. DeGroote Chair in Stem Cell Biology. This work was supported by a grant from the Ontario Research and Development Challenge Fund (ORDCF) to G.L. and by CIHR and NCIC to M.Bh. We also are grateful for the help of L. Gallacher and R. Mondeh with culture assistance, the Krembil Centre at the Robarts and M. Sibly and J. Trowbridge for useful suggestions, and A. Nagy, J. Rossant, M. Gertsenstein, K. Vinterstein, M. Mileikovsky and J. Draper for providing the CA1 human ES cell line.

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Author notes

  1. Pablo Menendez

    Present address: Present address: Spanish Stem Cell Bank-Andalucian Branch, Instituto de Investigaciones Biomedicas, Granada 18100, Spain.,

  2. Sean C. Bendall and Morag H. Stewart: These authors contributed equally to this work.

Authors and Affiliations

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

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

  2. Department of Biochemistry, Don Rix Protein Identification Facility, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 5C1, Canada,

    Sean C. Bendall, Dustin George & Gilles Lajoie

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Correspondence to Mickie Bhatia.

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This file contains Supplementary Figures 1-7 with Legends and Supplementary Tables 1-2. (PDF 9774 kb)

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Bendall, S., Stewart, M., Menendez, P. et al. IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro. Nature 448, 1015–1021 (2007). https://doi.org/10.1038/nature06027

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