TRANsCre-DIONE transdifferentiates scar-forming reactive astrocytes into functional motor neurons

An, H.; Lee, H.-L.; Cho, D.-W.; Hong, J.; Lee, H. Y.; Lee, J. M.; Woo, J.; Lee, J.; Park, M.; Yang, Y.-S.; Han, S.-C.; Ha, Y.; Lee, C. J.

doi:10.1101/2020.07.24.215160

bioRxiv · 10.1101/2020.07.24.215160

TRANsCre-DIONE transdifferentiates scar-forming reactive astrocytes into functional motor neurons

An, H.·Lee, H.-L.·Cho, D.-W.·Hong, J.·Lee, H. Y.·Lee, J. M.·Woo, J.·Lee, J.·Park, M.·Yang, Y.-S.·Han, S.-C.·Ha, Y.·Lee, C. J.

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Abstract

In spinal cord injury (SCI), the scar-forming reactive astrocytes with upregulated GFAP proliferate aberrantly near the injury site, allowing themselves as a prime target for transdifferentiation into neurons to replenish dead neurons. However, the conventional use of GFAP promoter to target reactive astrocytes has two inherent problems: inadvertent conversion of normal astrocytes and low efficiency due to progressive weakening of promoter activity during transdifferentiation. Here, we report that the scar-forming reactive astrocytes are selectively transdifferentiated into neurons with 87% efficiency and 96% specificity via TRANsCre-DIONE, a combination of the split-Cre system under two different promoters of GFAP and Lcn2 and a Cre-loxP-dependent inversion and expression of Neurog2 under the strong EF1 promoter. After SCI, TRANsCre-DIONE caused transdifferentiation into Isl1-positive motor neurons, reduced astrogliosis, enhanced regeneration in surrounding cells, and a significant motor recovery. Our study proposes TRANsCre-DIONE as the next-generation therapeutic approach for patients suffering from SCI. HighlightsTRANsCre-DIONE converts reactive astrocyte into neuron by over-expression of Neurog2 Reactive astrocytes are targeted using split-Cre under two promoters, GFAP and Lcn2 TRANsCre-DIONE reduces reactivity, replaces dead neurons and alleviates symptom of SCI Transdifferentiated-neurons are GABA+ in the striatum and Isl1+ in the spinal cord

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An, H., Lee, H.-L., Cho, D.-W., Hong, J., Lee, H. Y., Lee, J. M., Woo, J., Lee, J., Park, M., Yang, Y.-S., Han, S.-C., Ha, Y., Lee, C. J.. 2020-07-25. TRANsCre-DIONE transdifferentiates scar-forming reactive astrocytes into functional motor neurons. https://doi.org/10.1101/2020.07.24.215160

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