Reversing Glial Scar Back To Neural Tissue Through NeuroD1-Mediated Astrocyte-To-Neuron Conversion

Zhang, Lechi; Zhang, Lei; Z, Guo; Zhang, Pei; Chen, Y; Zhang, F; Cai, Ailong; Yk, Mok; G, Lee; Swaminnathan,; Wang, F; Bai, Yang; Chen, G

doi:10.1101/261438

Cited by 17 publications

(28 citation statements)

References 52 publications

(69 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1C). Interestingly, like that reported in rodent models (Chen et al, 2019; Zhang et al, 2018), we found that some NeuroD1-GFP infected cells were immunopositive for both GFAP (red) and NeuN (blue) (Fig. 1D), suggesting a transitional stage in-between astrocytes and neurons during the conversion process.…”

Section: Resultssupporting

confidence: 86%

“…It appears that both NeuN+/GFAP+ double positive cells and NeuN-/GFAP-double negative cells were transitional cells during AtN conversion process. These results suggest that overexpression of NeuroD1 in the astrocytes of monkey brains can convert them into neurons, similar to that found in the mouse brains (Chen et al, 2019; Guo et al, 2014; Zhang et al, 2018).…”

Section: Resultssupporting

confidence: 83%

“…We have previously demonstrated that reactive astrocytes inside mouse brains can be directly converted into functional neurons through expressing a single neural transcription factor NeuroD1 (Chen et al, 2019; Guo et al, 2014; Zhang et al, 2018). Because mouse brains are far different from human brains, it is uncertain whether such in vivo cell conversion technology would be applicable for future human clinical trials.…”

Section: Resultsmentioning

confidence: 99%

“…Our group previously reported that in vivo overexpression of a single neural transcription factor NeuroD1 can convert endogenous glial cells directly into functional neurons (Guo et al, 2014), providing a new approach for neural repair in the brain and spinal cord. Our more recent studies also demonstrated that NeuroD1 AAV-based gene therapy has great potential in repairing the ischemic injured or stab lesioned mouse cortex through direct in vivo astrocyte-to-neuron conversion (Chen et al, 2019; Zhang et al, 2018). Besides NeuroD1, other groups have reported that expression of transcription factors Ngn2, Ascl1, Sox2, or combinations of factors can also convert internal glial cells into neurons in the brain or spinal cord (Gascon et al, 2016; Grande et al, 2013; Jorstad et al, 2017; Liu et al, 2015; Niu et al, 2015; Niu et al, 2013; Pereira et al, 2017; Rivetti di Val Cervo et al, 2017; Su et al, 2014).…”

Section: Introductionmentioning

confidence: 90%

See 3 more Smart Citations

In Vivo Neuroregeneration to Treat Ischemic Stroke in Adult Non-Human Primate Brains through NeuroD1 AAV-based Gene Therapy

Yang

Feng

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Stroke is a leading cause of death and disability but most of the clinical trials have failed in the past, despite our increasing understanding of the molecular and pathological mechanisms underlying stroke. While many signaling pathways have been identified in the aftermath of stroke, the majority of current approaches are focusing on neural protection rather than neuroregeneration. In this study, we report an in vivo neural regeneration approach to convert brain internal reactive astrocytes into neurons through ectopic expression of a neural transcription factor NeuroD1 in adult non-human primate (NHP) brains following ischemic stroke. We demonstrate that NeuroD1 AAV-based gene therapy can convert reactive astrocytes into neurons with high efficiency (90%), but astrocytes are never depleted in the NeuroD1-expressed areas, consistent with the proliferative capability of astrocytes. The NeuroD1-mediated in vivo astrocyte-to-neuron (AtN) conversion in monkey cortex following ischemic stroke increased local neuronal density, reduced reactive microglia, and surprisingly protected parvalbumin interneurons in the converted areas. The NeuroD1 gene therapy showed a broad time window, from 10 days to 30 days following ischemic stroke, in terms of exerting its neuroregenerative and neuroprotective effects. The cortical astrocyte-converted neurons also showed Tbr1+ cortical neuron identity, similar to our earlier findings in rodent animal models. Unexpectedly, NeuroD1 expression in converted neurons showed a significant decrease after 6 months of viral infection, suggesting a potential self-regulatory mechanism of NeuroD1 in adult mature neurons of NHPs. These results suggest that in vivo cell conversion through NeuroD1-based gene therapy may be an effective approach to regenerate new neurons in adult primate brains for tissue repair.

show abstract

Section: Resultssupporting

confidence: 86%

Section: Resultssupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

See 2 more Smart Citations

In Vivo Neuroregeneration to Treat Ischemic Stroke in Adult Non-Human Primate Brains through NeuroD1 AAV-based Gene Therapy

Yang

Feng

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Our group has previously demonstrated that the neurogenic transcription factor NeuroD1 can reprogram reactive astrocytes into functional neurons in the stab-injured brain and in a mouse model for Alzheimer's disease (Guo et al, 2014). Following studies demonstrated that NeuroD1-mediated in vivo astrocyte-to-neuron conversion can reverse glial scar back to neural tissue (Zhang et al, 2018) and repair the damaged motor cortex after ischemic stroke . The major goal of the current study is to determine whether NeuroD1 can reprogram reactive astrocytes into functional neurons in the injured spinal cord.…”

Section: Introductionmentioning

confidence: 99%

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

Puls

Ding

Pan

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

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:

show abstract

Lithium‐loaded GelMA‐Phosphate glass fibre constructs: Implications for astrocyte response

Keskin‐Erdogan,

Mandakhbayar,

Jin

et al. 2024

J Biomedical Materials Res

View full text Add to dashboard Cite

Combinations of different biomaterials with their own advantages as well as functionalization with other components have long been implemented in tissue engineering to improve the performance of the overall material. Biomaterials, particularly hydrogel platforms, have shown great potential for delivering compounds such as drugs, growth factors, and neurotrophic factors, as well as cells, in neural tissue engineering applications. In central the nervous system, astrocyte reactivity and glial scar formation are significant and complex challenges to tackle for neural and functional recovery. GelMA hydrogel‐based tissue constructs have been developed in this study and combined with two different formulations of phosphate glass fibers (PGFs) (with Fe3+ or Ti2+ oxide) to impose physical and mechanical cues for modulating astrocyte cell behavior. This study was also aimed at investigating the effects of lithium‐loaded GelMA‐PGFs hydrogels in alleviating astrocyte reactivity and glial scar formation offering novel perspectives for neural tissue engineering applications. The rationale behind introducing lithium is driven by its long‐proven therapeutic benefits in mental disorders, and neuroprotective and pronounced anti‐inflammatory properties. The optimal concentrations of lithium and LPS were determined in vitro on primary rat astrocytes. Furthermore, qPCR was conducted for gene expression analysis of GFAP and IL‐6 markers on primary astrocytes cultured 3D into GelMA and GelMA‐PGFs hydrogels with and without lithium and in vitro stimulated with LPS for astrocyte reactivity. The results suggest that the combination of bioactive phosphate‐based glass fibers and lithium loading into GelMA structures may impact GFAP expression and early IL‐6 expression. Furthermore, GelMA‐PGFs (Fe) constructs have shown improved performance in modulating glial scarring over GFAP regulation.

show abstract

Reversing Glial Scar Back To Neural Tissue Through NeuroD1-Mediated Astrocyte-To-Neuron Conversion

Cited by 17 publications

References 52 publications

In Vivo Neuroregeneration to Treat Ischemic Stroke in Adult Non-Human Primate Brains through NeuroD1 AAV-based Gene Therapy

In Vivo Neuroregeneration to Treat Ischemic Stroke in Adult Non-Human Primate Brains through NeuroD1 AAV-based Gene Therapy

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

Lithium‐loaded GelMA‐Phosphate glass fibre constructs: Implications for astrocyte response

Contact Info

Product

Resources

About