HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

OPEN ACCESS ARTICLE

This Article Free via Open Access: OA OA Full Text Full Text (PDF) Supplemental Data OA All Versions of this Article: 2008-0293v1 26/12/3086    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Okada, Y. Articles by Okano, H. Search for Related Content PubMed PubMed Citation Articles by Okada, Y. Articles by Okano, H.

EMBRYONIC STEM CELLS/INDUCED PLURIPOTENT STEM CELLS

Spatiotemporal Recapitulation of Central Nervous System Development by Murine Embryonic Stem Cell-Derived Neural Stem/Progenitor Cells

^aDepartment of Physiology, Keio University, School of Medicine, Shinjuku-ku, Tokyo, Japan;
^bDepartment of Neurology, Nagoya University, Graduate School of Medicine, Showa-ku, Nagoya, Japan;
^cDepartment of Neurology, Tohoku University, Graduate School of Medicine, Aoba-ku, Sendai, Japan

Key Words. Neural stem/progenitor cells • Embryonic stem cells • Neurosphere • Temporal identity • Spatial identity • Regenerative medicine

Correspondence: Correspondence: Hideyuki Okano, M.D., Ph.D., Department of Physiology, Keio University, School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. Telephone: +81-3-5363-3747; Fax: +81-3-3357-5445; e-mail: hidokano{at}sc.itc.keio.ac.jp

Received on March 25, 2008; accepted for publication on August 12, 2008.

First published online in STEM CELLS EXPRESS  August 28, 2008.

Neural stem/progenitor cells (NS/PCs) can generate a wide variety of neural cells. However, their fates are generally restricted, depending on the time and location of NS/PC origin. Here we demonstrate that we can recapitulate the spatiotemporal regulation of central nervous system (CNS) development in vitro by using a neurosphere-based culture system of embryonic stem (ES) cell-derived NS/PCs. This ES cell-derived neurosphere system enables the efficient derivation of highly neurogenic fibroblast growth factor-responsive NS/PCs with early temporal identities and high cell-fate plasticity. Over repeated passages, these NS/PCs exhibit temporal progression, becoming epidermal growth factor-responsive gliogenic NS/PCs with late temporal identities; this change is accompanied by an alteration in the epigenetic status of the glial fibrillary acidic protein promoter, similar to that observed in the developing brain. Moreover, the rostrocaudal and dorsoventral spatial identities of the NS/PCs can be successfully regulated by sequential administration of several morphogens. These NS/PCs can differentiate into early-born projection neurons, including cholinergic, catecholaminergic, serotonergic, and motor neurons, that exhibit action potentials in vitro. Finally, these NS/PCs differentiate into neurons that form synaptic contacts with host neurons after their transplantation into wild-type and disease model animals. Thus, this culture system can be used to obtain specific neurons from ES cells, is a simple and powerful tool for investigating the underlying mechanisms of CNS development, and is applicable to regenerative treatment for neurological disorders.

Disclosure of potential conflicts of interest is found at the end of this article.