| Autor: |
Chen, Yu-Chen, Ma, Ning-Xin, Pei, Zi-Fei, Wu, Zheng, Do-Monte, Fabricio H., Keefe, Susan, Yellin, Emma, Chen, Miranda S., Yin, Jiu-Chao, Lee, Grace, Minier-Toribio, Angélica, Hu, Yi, Bai, Yu-Ting, Lee, Kathryn, Quirk, Gregory J., Chen, Gong |
| Zdroj: |
Molecular Therapy; January 2020, Vol. 28 Issue: 1 p217-234, 18p |
| Abstrakt: |
Adult mammalian brains have largely lost neuroregeneration capability except for a few niches. Previous studies have converted glial cells into neurons, but the total number of neurons generated is limited and the therapeutic potential is unclear. Here, we demonstrate that NeuroD1-mediated in situastrocyte-to-neuron conversion can regenerate a large number of functional new neurons after ischemic injury. Specifically, using NeuroD1 adeno-associated virus (AAV)-based gene therapy, we were able to regenerate one third of the total lost neurons caused by ischemic injury and simultaneously protect another one third of injured neurons, leading to a significant neuronal recovery. RNA sequencing and immunostaining confirmed neuronal recovery after cell conversion at both the mRNA level and protein level. Brain slice recordings found that the astrocyte-converted neurons showed robust action potentials and synaptic responses at 2 months after NeuroD1 expression. Anterograde and retrograde tracing revealed long-range axonal projections from astrocyte-converted neurons to their target regions in a time-dependent manner. Behavioral analyses showed a significant improvement of both motor and cognitive functions after cell conversion. Together, these results demonstrate that in vivocell conversion technology through NeuroD1-based gene therapy can regenerate a large number of functional new neurons to restore lost neuronal functions after injury. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
