Wild-type but not mutant SOD1 transgenic astrocytes promote the efficient generation of motor neuron progenitors from mouse embryonic stem cells

Background

The efficient derivation of mature (Hb9+) motor neurons from embryonic stem cells is a sought-after goal in the understanding, and potential treatment, of motor neuron diseases. Conditions that promote the robust generation of motor neuron progenitors from embryonic stem cells and that promote the survival of differentiated motor neurons ex vivo are likely, therefore, to be critical in future biological/therapeutic/screening approaches. Previous studies have shown that astrocytes have a protective effect on differentiated motor neurons (in vivo and ex vivo), but it remains unclear whether astrocytes also play a beneficial role in the support of motor neuron progenitors. Here we explore the effect of murine astrocyte-conditioned medium on monolayer cultures of mouse embryonic stem cell-derived motor neuron progenitors.

Results

Our data show that wild-type astrocyte-conditioned medium significantly increases the number of Olig2+/Hb9- progenitors, which subsequently differentiate into Hb9+/Islet1+ post-mitotic motor neurons. Intriguingly, while astrocyte-conditioned medium derived from mice transgenic for wild-type human SOD1 mimics the effect of wild-type astrocytes, conditioned medium derived from astrocytes carrying an amyotrophic lateral sclerosis-related SOD1-G93A mutation shows no such beneficial effect. The effect of astrocyte-conditioned medium, moreover, is specific to motor neurons: we find that interneurons generated from mouse embryonic stem cells are unaffected by conditioned media from any type of astrocyte.

Conclusions

Our study indicates that conditioned medium derived from wild type astrocytes enhances the efficient generation of motor neurons from mouse embryonic stem cells by enhancing motor neuron progenitors. In contrast, conditioned medium from SOD1-G93A astrocytes does not show a similar enhancing effect.