1. McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, and Department of Biochemistry, McMaster University, Hamilton, Ontario L8N 3Z5, Canada
2. Don Rix Protein Identification Facility, Department of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 5C1, Canada
3. These authors contributed equally to this work.
4. 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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