Article
- The EMBO Journal (2007) 26, 4744 - 4755
- doi:10.1038/sj.emboj.7601896
Published online: 18 October 2007
Subject Categories:
Niche-mediated control of human embryonic stem cell self-renewal and differentiation
Raheem Peerani1,2,a, Balaji M Rao1,ab, Celine Bauwens1,2, Ting Yin1, Geoffrey A Wood3, Andras Nagy4,5, Eugenia Kumacheva6 and Peter W Zandstra1,2
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada
- Centre for Modeling Human Disease, Toronto Centre for Phenogenomics, Toronto, Ontario, Canada
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
- Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada
- Department of Chemistry, University of Toronto, Toronto, Ontario, Canada
Correspondence to:
Peter W Zandstra, Institute of Biomaterials and Biomedical Engineering, University of Toronto, TD-CCBR Rm 1116, 160 College Street East, 11th Floor, Toronto, Ontario, Canada M5S 3E1. Tel.: +416 978 8888; Fax: +416 978 2666; E-mail: peter.zandstra@utoronto.ca
aThese authors contributed equally to this work
bPresent Address: Department of Chemical and Biomolecular Engineering, North Carolina State University, Box 7905, Engineering Building I, 911 Partners Way, Raleigh, NC 27695, USA
Received 28 May 2007; Accepted 26 September 2007
Abstract
Complexity in the spatial organization of human embryonic stem cell (hESC) cultures creates heterogeneous microenvironments (niches) that influence hESC fate. This study demonstrates that the rate and trajectory of hESC differentiation can be controlled by engineering hESC niche properties. Niche size and composition regulate the balance between differentiation-inducing and -inhibiting factors. Mechanistically, a niche size-dependent spatial gradient of Smad1 signaling is generated as a result of antagonistic interactions between hESCs and hESC-derived extra-embryonic endoderm (ExE). These interactions are mediated by the localized secretion of bone morphogenetic protein-2 (BMP2) by ExE and its antagonist, growth differentiation factor-3 (GDF3) by hESCs. Micropatterning of hESCs treated with small interfering (si) RNA against GDF3, BMP2 and Smad1, as well treatments with a Rho-associated kinase (ROCK) inhibitor demonstrate that independent control of Smad1 activation can rescue the colony size-dependent differentiation of hESCs. Our results illustrate, for the first time, a role for Smad1 in the integration of spatial information and in the niche-size-dependent control of hESC self-renewal and differentiation.
Keywords:
- embryonic stem cell,
- micropatterning,
- niche,
- self-renewal,
- Smad signaling
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