Engineering Glia to Regenerate Neurons
We have developed strategies to stimulate regeneration of neurons in vivo in the adult mouse retina. This is done by overexpressing the proneural transcription factor Ascl1 in Muller glia. Ascl1 stimulates Muller glia to reprogram into neurogenic progenitors capable of producing functional bipolar neurons (Jorstad, 2017 Nature). We found that we combining Ascl1 with another transcription factor (Atoh1/7), shifts the cell fate off regenerated neurons from bipolars to immature retinal ganglion cells (Todd, et al. 2021, Cell Reports). Recently, we followed this up by demonstrating that retinal glial-to-retinal ganglion cell reprogramming can be significantly enhanced by using the developmental transcription 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
An example of a retinal ganglion cell regenerated from Muller glia.
Glia in the mammalian retina naturally respond to injury or neurodegeneration by undergoing an inflammatory response rather than a regenerative one. We have been developing immunomodulation strategies to combine with our regeneration approaches to enhance retinal repair. Using single-cell transcriptomics, transgenic mice, and pharmacological approaches we found that microglia drive Muller glia polarization to an inflammatory state rather than a neurogenic one. Indeed, we found that ablation of microglia significantly enhanced the neurogenic capacity of Muller glia (Todd, et al. 2020 Cell Reports). This finding implicates the neuroimmune system as a key component of the regenerative response of the mammalian retina. However, little is known about the broader neuroimmune interface in retinal repair strategies such as endogenous regeneration. My laboratory will seek to better understand the neuroimmune axis during retinal regeneration and to develop immunomodulation strategies to improve the regenerative capacity of the retina.
Single-cell RNA-sequencing data analyzing the molecular response of Muller glia to injury and identifying substates of inflammation vs. neurogenic responses.