Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell–derived neocortex
Edited by Chen-Ming Fan, Carnegie Institution of Washington, Baltimore, MD, and accepted by the Editorial Board October 17, 2013 (received for review August 21, 2013)
Significance
Using 3D culture of human ES cells, we show new self-organizing aspects of human corticogenesis: spontaneous development of intracortical polarity, curving morphology, and complex zone separations. Moreover, this culture generates species-specific progenitors, outer radial glia, which are abundantly present in the human, but not mouse, neocortex. Our study suggests an unexpectedly wide range of self-organizing events that are driven by internal programs in human neocortex development.
Abstract
Here, using further optimized 3D culture that allows highly selective induction and long-term growth of human ES cell (hESC)-derived cortical neuroepithelium, we demonstrate unique aspects of self-organization in human neocorticogenesis. Self-organized cortical tissue spontaneously forms a polarity along the dorsocaudal-ventrorostral axis and undergoes region-specific rolling morphogenesis that generates a semispherical structure. The neuroepithelium self-forms a multilayered structure including three neuronal zones (subplate, cortical plate, and Cajal-Retzius cell zones) and three progenitor zones (ventricular, subventricular, and intermediate zones) in the same apical-basal order as seen in the human fetal cortex in the early second trimester. In the cortical plate, late-born neurons tend to localize more basally to early-born neurons, consistent with the inside-out pattern seen in vivo. Furthermore, the outer subventricular zone contains basal progenitors that share characteristics with outer radial glia abundantly found in the human, but not mouse, fetal brain. Thus, human neocorticogenesis involves intrinsic programs that enable the emergence of complex neocortical features.
Acknowledgments
We thank Keiko Muguruma, Nicholas Love, Momoko Watanabe, and Atsushi Kuwahara for invaluable comments and Jürgen Knoblich for in-depth discussion on his recent study. T.K. is grateful to Seiichi Yokoyama, Yoshiharu Mimamitake, Yasuhiro Kita, Teruyoshi Inoue, and Kumiko Kadoshima for continuous encouragement during this project. This work was supported by grants-in-aid from Ministry of Education, Culture, Sports, Science and Technology (to Y.S. and M.E.), and by the Core Program for Disease Modeling Using iPS Cells (to Y.S.), and the Network Program for Realization of Regenerative Medicine (to Y.S.) from Japan Science and Technology Agency.
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Published online: November 25, 2013
Published in issue: December 10, 2013
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Acknowledgments
We thank Keiko Muguruma, Nicholas Love, Momoko Watanabe, and Atsushi Kuwahara for invaluable comments and Jürgen Knoblich for in-depth discussion on his recent study. T.K. is grateful to Seiichi Yokoyama, Yoshiharu Mimamitake, Yasuhiro Kita, Teruyoshi Inoue, and Kumiko Kadoshima for continuous encouragement during this project. This work was supported by grants-in-aid from Ministry of Education, Culture, Sports, Science and Technology (to Y.S. and M.E.), and by the Core Program for Disease Modeling Using iPS Cells (to Y.S.), and the Network Program for Realization of Regenerative Medicine (to Y.S.) from Japan Science and Technology Agency.
Notes
This article is a PNAS Direct Submission. C.-M.F. is a guest editor invited by the Editorial Board.
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Competing Interests
The authors declare no conflict of interest.
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Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell–derived neocortex, Proc. Natl. Acad. Sci. U.S.A.
110 (50) 20284-20289,
https://doi.org/10.1073/pnas.1315710110
(2013).
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