The great hope for embryonic stem cell (ESC) research is that scientists will be able to develop effective strategies for coaxing these cells to develop into a wide variety of mature cell types and tissues, which could in turn be used for clinical studies or even outright transplantation into patients.
Although this field is still in its infancy, there have been promising signs of progress. For instance, Yoshiki Sasai’s team at the RIKEN Center for Developmental Biology in Kobe recently described a technique for stem cell cultivation, SFEB, which enables the reliable derivation of neuronal precursors from cultured ESCs (1). However, this technique has shown only limited efficiency in obtaining some particular cell types, such as cerebral cortical neurons.
To improve their method, Sasai and colleagues have introduced a new twist—cultivating dissociated mouse ESCs under conditions that favor unrestricted aggregation in three dimensions, rather than in adherent cultures on a flat surface (2). The results of their ‘quick aggregation’ SFEB (SFEBq) method are striking—nearly 95% of the resulting neuronal progenitors differentiated into sheets of neuroepithelial cells, brain tissue precursors with a distinctive polarized structure.
With further cultivation, these sheets reformed into spherical clusters that subsequently yielded functional cortical neurons, both in culture and after transplantation into mouse brains. To Sasai’s surprise, they even observed network behavior in their cultures. “The induced cortical tissues started to exhibit synchronized neural activity over a range of more than one millimeter,” he says, “which is characteristic of the neural activity seen in the neonatal cortex.”
But there were other surprises as well. By examining changes over time in gene expression profiles in their SFEBq cultures, Sasai’s team found that their ESC-derived cortical neuron progenitors were naturally entering into a stepwise developmental program of specialized layer formation that closely resembles normal embryonic cortical development (Fig. 1). “This is self-formation of a highly ordered pattern from patternless cells, which is quite impressive to me,” says Sasai. “In other words, it is the programmed nature of these cells to form such structures.”
The ability to recapitulate and even control the complex developmental processes underlying tissue formation in culture is exciting from both a research and a medical perspective, and Sasai’s team is now focused on better understanding this phenomenon. “I hope that this direction of stem cell technology development may contribute to progress in drug development and toxicology … as well as understanding of pathogenesis of brain diseases,” he says.
Reference
1. Watanabe, K., Kamiya, D., Nishiyama, A., Katayama, T., Nozaki, S., Kawasaki, H., Watanabe, Y., Mizuseki, K. & Sasai, Y. Directed differentiatoin of telencephalic precursors from embryonic stem cells. Nature Neuroscience 8, 288–296 (2005).
2. Eiraku, M., Watanabe, K., Matsuo-Takasaki, M., Kawada, M., Yonemura, S., Matsumura, M., Wataya, T., Nishiyama, A., Muguruma, K. & Sasai, Y. Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell 3, 519–532 (2008).
The corresponding author for this highlight is based at the RIKEN Laboratory for Organogenesis and Neurogenesis
