The p53 Pathway Controls SOX2-Mediated Reprogramming in the Adult Mouse Spinal Cord

Wang, Lei Lei; Su, Zhida; Tai, Wenjiao; Zou, Yuhua; Xu, Xiao Ming; Zhang, Chun Li

doi:10.1016/j.celrep.2016.09.038

Cited by 89 publications

(101 citation statements)

References 59 publications

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“…Neuroregeneration in adult mammalian CNS has been proved to be one of the most difficult tasks in the entire regenerative medicine field, largely because neurons cannot divide to regenerate themselves and external cell transplantation yields very low number of functional new neurons (Goldman, 2016). To overcome the limitations of cell transplantation therapy, we, together with other research groups, have developed in vivo cell conversion technology to regenerate functional new neurons from endogenous glial cells for brain repair (Chen et al, 2019; Gascon et al, 2016; Guo et al, 2014; Karow et al, 2018; Liu et al, 2015; Niu et al, 2015; Niu et al, 2018; Pereira et al, 2017; Torper et al, 2015; Wang et al, 2016; Zhang et al, 2018). While stab injury model has been commonly used in various in vivo cell conversion studies, we have previously demonstrated in a mouse Alzheimer’s disease model that NeuroD1 can convert reactive astrocytes into functional neurons in 14-month old AD mouse brains (Guo et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

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

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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.

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Section: Discussionmentioning

confidence: 99%

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

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“…Studies of regenerating zebrafish retina suggest that Cdkn1a upregulation stalls MG in a dedifferentiated state, and limits MG proliferation (Zhang et al, ). Furthermore, Cdkn1a might limit Sox2‐mediated reprogramming in glia‐derived neuronal regeneration of the mammalian spinal cord (Wang et al, ). Various cell changes can induce expression of Cdkn1a, which is presumed to inhibit cell growth and has been suggested as a regulator of cell survival and senescence.…”

Section: Discussionmentioning

confidence: 99%

Prospective purification and characterization of Müller glia in the mouse retina regeneration assay

Patrick

Karl

2017

Glia

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Reactive gliosis is an umbrella term for various glia functions in neurodegenerative diseases and upon injury. Specifically, Müller glia (MG) in some species readily regenerate retinal neurons to restore vision loss after insult, whereas mammalian MG respond by reactive gliosis-a heterogeneous response which frequently includes cell hypertrophy and proliferation. Limited regeneration has been stimulated in mammals, with a higher propensity in young MG, and in vitro compared to in vivo, but the underlying processes are unknown. To facilitate studies on the mechanisms regulating and limiting glia functions, we developed a strategy to purify glia and their progeny by fluorescence-activated cell sorting. Dual-transgenic nuclear reporter mice, which label neurons and glia with red and green fluorescent proteins, respectively, have enabled MG enrichment up to 93% purity. We applied this approach to MG in a mouse retina regeneration ex vivo assay. Combined cell size and cell cycle analysis indicates that most MG hypertrophy and a subpopulation proliferates which, over time, become even larger in cell size than the ones that do not proliferate. MG undergo timed differential genomic changes in genes controlling stemness and neurogenic competence; and glial markers are downregulated. Genes that are potentially required for, or associated with, regeneration and reactive gliosis are differentially regulated by retina explant culture time, epidermal growth factor stimulation, and animal age. Thus, MG enrichment facilitates cellular and molecular studies which, in combination with the mouse retina regeneration assay, provide an experimental approach for deciphering mechanisms that possibly regulate reactive gliosis and limit regeneration in mammals.

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“…We demonstrate here that NeuroD1 converts reactive astrocytes into primarily Tlx3-positive glutamatergic neurons in the dorsal horn of the injured spinal cord. Interestingly, Sox2converted neurons in the injured spinal cord are also mainly glutamatergic (Wang et al, 2016), raising the possibility that glutamatergic neurons might be a default subtype of converted neurons. On the other hand, one cannot ignore the small yet significant component of GABAergic neurons (~10-15%) generated by NeuroD1 in the dorsal horn of spinal cord, which we found to be roughly equal to the population in our non-injured control and might still play a meaningful role in the local circuitry.…”

Section: Generation Of Neuronal Subtypes Via Neurod1-mediated Conversionmentioning

confidence: 99%

“…With additional treatment of neurotrophic factors, Sox2-converted neurons can express several neuronal subtype markers, but predominately VGluT, a marker for glutamatergic neurons (Wang et al, 2016).…”

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

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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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The p53 Pathway Controls SOX2-Mediated Reprogramming in the Adult Mouse Spinal Cord

Cited by 89 publications

References 59 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

Prospective purification and characterization of Müller glia in the mouse retina regeneration assay

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

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