In Vivo Reprogramming for CNS Repair: Regenerating Neurons from Endogenous Glial Cells

Li, Hedong; Chen, Gong

doi:10.1016/j.neuron.2016.08.004

Cited by 134 publications

(100 citation statements)

References 127 publications

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“…Neuronal conversion can be achieved by several neurogenic transcription factors (Li and Chen, 2016). Besides NeuroD1, Sox2, Ngn2, and Ascl1 have all been reported to convert glial cells into neurons (Gascon et al, 2016;Grande et al, 2013;Guo et al, 2014;Heinrich et al, 2014;Liu et al, 2015;Niu et al, 2013;Su et al, 2014).…”

Section: Distinct Functions Of Neurod1 During Neuronal Conversionmentioning

confidence: 99%

“…Neuronal conversion can be achieved by several neurogenic transcription factors (Li and Chen, 2016 ). An earlier report also showed that Ngn2-expressing retrovirus was able to promote neurogenesis in the injured spinal cord, but the number of newly generated neurons greatly decreases over time even when combined with growth factor treatment (Ohori et al, 2006).…”

Section: Distinct Functions Of Neurod1 During Neuronal Conversionmentioning

confidence: 99%

“…In vivo neuronal reprogramming has recently emerged as a novel technology to regenerate functional new neurons from endogenous glial cells by overexpressing neurogenic transcription factors in the CNS (Barker et al, 2018;Gascon et al, 2016;Grande et al, 2013;Guo et al, 2014;Lei et al, 2019;Li and Chen, 2016;Liu et al, 2015;Niu et al, 2013). In the injured spinal cord, a combination of growth factor treatment and forced expression of the neurogenic transcription factor Neurogenin 2 (Ngn2) has been reported to stimulate neurogenesis from neural progenitors (Ohori et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Regeneration of dorsal spinal cord neurons after injury viain situNeuroD1-mediated astrocyte-to-neuron conversion

Puls

Ding

Pan

et al. 2019

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Spinal cord injury (SCI) often leads to impaired motor and sensory functions, partially because the injury-induced neuronal loss cannot be easily replenished through endogenous mechanisms. In vivo neuronal reprogramming has emerged as a novel technology to regenerate neurons from endogenous glial cells by forced expression of neurogenic transcription factors.We have previously demonstrated successful astrocyte-to-neuron conversion in mouse brains with injury or Alzheimer's disease by overexpressing a single neural transcription factor NeuroD1 via retroviruses. Here we demonstrate regeneration of dorsal spinal cord neurons from reactive astrocytes after SCI via adeno-associated virus (AAV), a more clinically relevant gene delivery system. We find that NeuroD1 converts reactive astrocytes into neurons in the dorsal horn of stab-injured spinal cord with high efficiency (~95%). Interestingly, NeuroD1converted neurons in the dorsal horn mostly acquire glutamatergic neuronal subtype, expressing spinal cord-specific markers such as Tlx3 but not brain-specific markers such as Tbr1, suggesting that the astrocytic lineage and local microenvironment affect the cell fate of conversion. Electrophysiological recordings show that the NeuroD1-converted neurons can functionally mature and integrate into local spinal cord circuitry by displaying repetitive action potentials and spontaneous synaptic responses. We further show that NeuroD1-mediated neuronal conversion can occur in the contusive SCI model, allowing future studies of evaluating this reprogramming technology for functional recovery after SCI. In conclusion, this study may suggest a paradigm shift for spinal cord repair using in vivo astrocyte-to-neuron conversion technology to generate functional neurons in the grey matter.3 Introduction:

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Section: Distinct Functions Of Neurod1 During Neuronal Conversionmentioning

confidence: 99%

Section: Distinct Functions Of Neurod1 During Neuronal Conversionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Regeneration of dorsal spinal cord neurons after injury viain situNeuroD1-mediated astrocyte-to-neuron conversion

Puls

Ding

Pan

et al. 2019

Preprint

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“…Here we demonstrated that NeuroD1-mediated astrocyte reprogramming results in the production of mature, active and regionally appropriate neurons that survive long term and correlate with motor improvement following cortical stroke. Previous studies have demonstrated the feasibility of direct cellular conversion in vivo [7,9,[12][13][14][22][23][24][25] but few have demonstrated improved behavioural outcomes following injury [12,17]. Using a foot fault task and gait analysis, we demonstrate that astrocyte-to-neuron reprogramming leads to functional improvement as early as three weeks post-reprogramming, and sustained long-term recovery.…”

Section: Discussionmentioning

confidence: 75%

Direct reprogramming of astrocytes to neurons leads to functional recovery after stroke

Livingston

Lee

Daniele

et al. 2020

Preprint

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Stroke is the leading cause of adult disability with few treatment options for stroke survivors. Astrocyte reprogramming to neurons enables the targeted in vivo generation of new cells at the site of injury and represents a novel approach for brain repair. A number of studies have demonstrated successful conversion of astrocytes to neurons in various models of brain injury and disease; however, the impact of this strategy on tissue and functional outcome following stroke is not well established. Using AAV delivery of the transcription factor NeuroD1, we reprogrammed astrocytes 7 days after endothelin-1 induced cortical stroke, and studied the long-term cellular and functional outcomes. We found that by 63 days post-stroke, 20% of neurons in the perilesional cortex were reprogrammed. Furthermore, reprogrammed neurons had matured into regionally appropriate neuronal subtypes. Importantly, this treatment was associated with improved functional outcome using the foot fault test and gait analysis. Together, our findings indicate that in vivo reprogramming is a promising regenerative approach for stroke repair.

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“…or of astrocytes through in vivo reprogramming [68] is a field under intense study and these vectors might have a distinct utility in this. Furthermore the stability of production and the lack of toxicity in producer cell lines or inactivation in human sera confers to these vectors the great advantage of being easily amenable for clinical use.…”

mentioning

confidence: 99%

Selective transduction of astrocytic and neuronal CNS subpopulations by lentiviral vectors pseudotyped with Chikungunya virus envelope

et al. 2017

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NHAs was observed. In vivo stereotaxic delivery in striatum, thalamus and hippocampus respectively in the adult rat brain revealed localised transduction restricted to striatal astrocytes and hippocampal dentate granule neurons. Transduction of different subtypes of granule neurons from precursor to post-mitotic stages of differentiation was evident in the sub-granular zone and dentate granule cell layer. No significant inflammatory response was observed, but comparable to that of VSV-G pseudotyped lentiviral vectors. Robust longterm expression followed for three months post-transduction along with absence of neuroinflammation, coupled to the selective and unique neuron/glial tropism indicates that these vectors could be useful for modelling and gene therapy studies in the CNS.

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In Vivo Reprogramming for CNS Repair: Regenerating Neurons from Endogenous Glial Cells

Cited by 134 publications

References 127 publications

Regeneration of dorsal spinal cord neurons after injury viain situNeuroD1-mediated astrocyte-to-neuron conversion

Regeneration of dorsal spinal cord neurons after injury viain situNeuroD1-mediated astrocyte-to-neuron conversion

Direct reprogramming of astrocytes to neurons leads to functional recovery after stroke

Selective transduction of astrocytic and neuronal CNS subpopulations by lentiviral vectors pseudotyped with Chikungunya virus envelope

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