Self-Organized Formation of Polarized Cortical Tissues from ESCs and Its Active Manipulation by Extrinsic Signals

Organogenesis and Neurogenesis Group, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan.
Cell stem cell (Impact Factor: 22.27). 12/2008; 3(5):519-32. DOI: 10.1016/j.stem.2008.09.002
Source: PubMed


Here, we demonstrate self-organized formation of apico-basally polarized cortical tissues from ESCs using an efficient three-dimensional aggregation culture (SFEBq culture). The generated cortical neurons are functional, transplantable, and capable of forming proper long-range connections in vivo and in vitro. The regional identity of the generated pallial tissues can be selectively controlled (into olfactory bulb, rostral and caudal cortices, hem, and choroid plexus) by secreted patterning factors such as Fgf, Wnt, and BMP. In addition, the in vivo-mimicking birth order of distinct cortical neurons permits the selective generation of particular layer-specific neurons by timed induction of cell-cycle exit. Importantly, cortical tissues generated from mouse and human ESCs form a self-organized structure that includes four distinct zones (ventricular, early and late cortical-plate, and Cajal-Retzius cell zones) along the apico-basal direction. Thus, spatial and temporal aspects of early corticogenesis are recapitulated and can be manipulated in this ESC culture.

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    • "Moreover, the presence of Shh or Shh agonists can give rise to ventral telencephalic progenitors from which cortical interneurons can differentiate (Germain et al., 2013; Maroof et al., 2013). Furthermore, hPSC-derived cortical progenitors generally acquire a caudal identity by default as shown by their pattern of projections when transplanted in mouse brains (Espuny-Camacho et al., 2013), yet they can be patterned to different cortical regions and respond to signalling cues when treated with morphogen agonists (Eiraku et al., 2008; Espuny-Camacho et al., 2013; Kadoshima et al., 2013). Moreover, whilst the temporal generation of neurons belonging to different layers is largely maintained in vitro and the presence of neurons belonging to all six layers has been reported, the contribution of each layer considerably varies depending on the method used (see (van den Ameele et al., 2014)). "
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    • "Human PSC-derived cortical progenitors start to generate neurons after a much longer period of about 4 weeks, instead of 6-8 days in the mouse. Similarly, the generation of distinct types of cortical neurons is also much protracted, requiring about 1 week in the mouse (Gaspard et al., 2008) but several months starting from human ESCs (Fig. 2C) (Eiraku et al., 2008; Espuny-Camacho et al., 2013; Gaspard et al., 2008; Kadoshima et al., 2013; Shi et al., 2012). Another distinctive feature proposed to link the development and evolution of human corticogenesis is the diversity of progenitors (Fig. 2A,B). "
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