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
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)). "
ABSTRACT: The in vitro derivation of regionally defined human neuron types from patient-derived stem cells is now established as a resource to investigate human development and disease. Characterisation of such neurons initially focused on the expression of developmentally regulated transcription factors and neural markers, in conjunction with the development of protocols to direct and chart the fate of differentiated neurons. However, crucial to the understanding and exploitation of this technology is to determine the degree to which neurons recapitulate the key functional features exhibited by their native counterparts, essential for determining their usefulness in modelling human physiology and disease in vitro. Here, we review the emerging data concerning functional properties of human pluripotent stem cell-derived excitatory cortical neurons, both in the context of maturation and regional specificity. This article is protected by copyright. All rights reserved.
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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). "
ABSTRACT: The human brain is arguably the most complex structure among living organisms. However, the specific mechanisms leading to this complexity remain incompletely understood, primarily because of the poor experimental accessibility of the human embryonic brain. Over recent years, technologies based on pluripotent stem cells (PSCs) have been developed to generate neural cells of various types. While the translational potential of PSC technologies for disease modeling and/or cell replacement therapies is usually put forward as a rationale for their utility, they are also opening novel windows for direct observation and experimentation of the basic mechanisms of human brain development. PSC-based studies have revealed that a number of cardinal features of neural ontogenesis are remarkably conserved in human models, which can be studied in a reductionist fashion. They have also revealed species-specific features, which constitute attractive lines of investigation to elucidate the mechanisms underlying the development of the human brain, and its link with evolution.
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- "Collectively, these results demonstrate that the onset of UL neuron generation is controlled by the termination of DL competence, which is propagated through post-mitotic DL neurons (Toma et al., 2014). Interestingly, this signal appears to act qualitatively rather than quantitatively in vivo, where only a few postmitotic DL neurons are required to induce UL neurogenesis (Toma et al., 2014), in contrast to the requirements in vitro (Shen et al., 2006; Eiraku et al., 2008; Gaspard et al., 2008; Kadoshima et al., 2013). These observations raise the possibility that this feedback signaling may be propagated by short-range signaling through cell–cell interactions. "
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