When it comes to researching and treating neurodegenerative diseases, some embryonic stem cells may be better than others. Neurons produced from different embryonic stem cell lines are different, according to a study by neuroscientists led by Thomas Südhof of the University of Texas Southwestern Medical Center and Yi Sun of the University of California, Los Angeles. Both lines studied produced functional neurons, but formed different kinds of synaptic networks and exhibited features characteristic of different parts of the brain.

As ES cells, HSF1 and HSF cell lines can form a wide variety of cell types. Nonetheless, the cell lines seem “preprogrammed” to become different subtypes of neurons, the researchers report in PNAS1. To reach this conclusion, the researchers developed methods to convert hES cells into relatively homogenous cultures of neurons. First, they generated cultures containing greater than 95% neural stem or progenitor cells, then used cell-sorting and -dissociation techniques to separate differentiated neurons from progenitors. When cocultured with neuron-support cells, these human neurons form functional neural networks, allowing researchers to study their electrophysiology.

HSF1-derived ES cells became forebrain neurons, while HSF6 ES cells produced mainly neurons characteristic of the hindbrain and midbrain. The cell lines produced neurons with different resting potential and also developed different types of synapses: HSF6-derived neurons formed relatively more excitatory synapses, forming glutamergic networks. HSF1-derived neurons formed primarily GABAergic networks and more inhibitory synapses

The cause of the differences is unknown. HSF1 was derived from a male embryo and HSF6 from a female embryo, but X-inactivation appears to have occurred properly in HSF6 cells. Epigenetic differences seem the most likely explanation. The scientists found significant expression differences in microRNA, small RNAs that regulate gene expression. Some two-fifths of microRNAs vary more than 2-fold between the lines, for all cell types studied (ES cells, neural progenitor cells and neurons). However, only four miRNAs had more than 4-fold differences in neurons differentiated from the two lines.

Embryonic stem cells may be the best source of neurons for research and potential therapies; other human sources include aborted fetuses, brain biopsies, or cadavers. These samples are highly variable and scarce, whereas embryonic stem cells can be propagated indefinitely and readily form neurons in culture. Though confirmation by other labs is still necessary, this work shows that differences between neurons from embryonic stem cell lines could be important for research and therapy. The next step will be understanding the causes of these differences and perhaps using that knowledge to better control differentiation.