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The Journal of Neuroscience, May 16, 2007, 27(20):5437-5447; doi:10.1523/JNEUROSCI.0300-07.2007

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Development/Plasticity/Repair
Adhesion Is Prerequisite, But Alone Insufficient, to Elicit Stem Cell Pluripotency

Phillip Karpowicz,¹ Tomoyuki Inoue,² Sue Runciman,² Brian Deveale,² Raewyn Seaberg,² Marina Gertsenstein,³ Lois Byers,³ Yojiro Yamanaka,³ Sandra Tondat,³ John Slevin,³ Seiji Hitoshi,⁴ Janet Rossant,³ and Derek van der Kooy²

¹Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5S 1A8, ²Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada M5S 3E1, ³Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5, and ⁴National Institute for Physiological Sciences, Okazaki, Aichi, 444-8585, Japan

Correspondence should be addressed to Phillip Karpowicz, Institute of Medical Science, Department of Molecular and Medical Genetics, 160 College Street, 11th Floor Donnelly Centre for Cellular and Biomolecular Research Building, University of Toronto, Toronto, Ontario, Canada M5S 3E1. Email: phillip.karpowicz{at}utoronto.ca

Primitive mammalian neural stem cells (NSCs), arising during the earliest stages of embryogenesis, possess pluripotency in embryo chimera assays in contrast to definitive NSCs found in the adult. We hypothesized that adhesive differences determine the association of stem cells with embryonic cells in chimera assays and hence their ability to contribute to later tissues. We show that primitive NSCs and definitive NSCs possess adhesive differences, resulting from differential cadherin expression, that lead to a double dissociation in outcomes after introduction into the early- versus midgestation embryo. Primitive NSCs are able to sort with the cells of the inner cell mass and thus contribute to early embryogenesis, in contrast to definitive NSCs, which cannot. Conversely, primitive NSCs sort away from cells of the embryonic day 9.5 telencephalon and are unable to contribute to neural tissues at midembryogenesis, in contrast to definitive NSCs, which can. Overcoming these adhesive differences by E-cadherin overexpression allows some definitive NSCs to integrate into the inner cell mass but is insufficient to allow them to contribute to later development. These adhesive differences suggest an evolving compartmentalization in multipotent NSCs during development and serve to illustrate the importance of cell–cell association for revealing cellular contribution.

Key words: neural stem cell; plasticity; transplantation; adhesion; cell fate; differentiation

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Received Jan. 23, 2007; revised March 19, 2007; accepted April 7, 2007.

Correspondence should be addressed to Phillip Karpowicz, Institute of Medical Science, Department of Molecular and Medical Genetics, 160 College Street, 11th Floor Donnelly Centre for Cellular and Biomolecular Research Building, University of Toronto, Toronto, Ontario, Canada M5S 3E1. Email: phillip.karpowicz{at}utoronto.ca

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