Engineering glia to regenerate neurons

Unlike in lower vertebrates the mammalian nervous system does not regenerate lost neurons. When neurons are lost to injury or disease in the retina it results in irreversible blindness. Therefore, an impetus exists to develop cell replacement strategies for vision restoration therapy.

We have developed strategies to stimulate regeneration of neurons in vivo in the adult mouse retina. This is done by forcing expression of the proneural transcription factor Ascl1 in Muller glia. Ascl1 stimulates Muller glia to reprogram into neurogenic progenitors capable of producing functional bipolar neurons. We have identified factors, such as Stat-signaling that can be modulated to enhance the regenerative potential of Muller glia to make bipolar neurons. However, most retinal diseases are due to loss of ganglion cells or photoreceptors, cell types not generated with Ascl1 alone.

We found that combining Ascl1 with another transcription factor, Atoh1, shifts the cell fate of regenerated neurons from bipolars to immature retinal ganglion cells. We recently followed this up by demonstrating that Glial-to-retinal ganglion cell reprogramming can be significantly enhanced by using the retinal ganglion-cell fate inducing factors Pou4f2 & Islet1.

This work sets the stage for testing other transcription factors in their ability to regenerate neurons of choice from Muller glia. A primary direction of the laboratory will be to further engineer glia to gain better control of the regeneration process. This work will make significant advances in developing endogenous cell replacement strategies in vision threatening diseases.