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Embryonic Stem Cells |
1 Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
2 Institute of Biomaterials and Biomedical Engineering, Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada
* To whom correspondence should be addressed. E-mail: peter.zandstra{at}utoronto.ca.
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Abstract |
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Highly ordered aggregates of cells, or niches, regulate stem cell fate. Specific tissue location need not be an obligate requirement for a stem cell niche, particularly during embryogenesis where cells exist in a dynamic environment. We investigated autoregulatory fixed-location independent processes controlling cell fate by analyzing spatial organization of embryonic stem cells (ESCs) using quantitative single-cell immunocytochemistry, and a computational approach involving Delaunay triangulation. ESC colonies demonstrated radial organization of phosphorylated signal transducer and activator of transcription 3 (STAT3), Nanog, and Oct4 (among others) in the presence and absence of exogenous leukemia inhibitory factor (LIF). Endogenous self-renewal signaling resulted from autocrine non-LIF gp130 ligands which buffered cells against differentiation upon exogenous LIF deprivation. Together with a radial organization of differential responsiveness to gp130 ligands within colonies, autocrine signaling produced a radial organization of self-renewal, generating a fixed-location independent autoregulatory niche. These findings reveal fundamental properties of niches, and elucidate mechanisms colonies of cells use to transition between fates during morphogenesis.
Key Words. autocrine signaling, embryonic stem cells, niche, self-renewal, stem cell biology
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