Differential neuronal reprogramming induced by NeuroD1 from astrocytes in grey matter versus white matter

Liu, Min Hui; Li, Wen; Zheng, Jia Jun; Xu, Yu; He, Qing-Yu; Chen, Gong

doi:10.4103/1673-5374.265185

Cited by 58 publications

(54 citation statements)

References 45 publications

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“…In our experiments using AAV, we rarely observed converted neurons in the white matter; using retrovirus, we observed some converted neurons in the white matter at early time points, but they rarely survived to 6 wpi. This has been similarly observed in cell conversion studies in the white matter (corpus callosum) of mouse brains (Liu et al, 2020). Reasons for the lack of conversion in the white matter in this study could include our targeted injection technique which delivers virus precisely into the dorsal horn of the grey matter or the lack of appropriate viral receptors in the white matter.…”

Section: Environmental Cues To Impact Neuronal Conversion In Additionsupporting

confidence: 69%

“…2A). Specifically, we used a Cre-Flex gene expression system, which contains two AAV vectors, with one encoding GFAP-Cre and the other encoding the transgene in reverse form flanked by double LoxP sites (FLEX vector) (Atasoy et al, 2008;Chen et al, 2018;Liu et al, 2015). Thus, when the two AAVs are co-injected into the spinal cord, Cre recombinase will be expressed in the infected reactive astrocytes and turn on the transgene expression in FLEX vector by flipping the transgene sequence into the correct form for transcription ( Fig.…”

Section: Neurod1 Reprograms Reactive Astrocytes Into Neurons In the Imentioning

confidence: 99%

“…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). Sox2 is expressed in neural progenitors and functions to maintain progenitor identity (Bani-Yaghoub et al, 2006;Bylund et al, 2003;Graham et al, 2003).…”

Section: Distinct Functions Of Neurod1 During Neuronal Conversionmentioning

confidence: 99%

“…This dual role of NeuroD1 during neuronal conversion and neuronal survival may explain its higher conversion efficiency over Sox2 and Ngn2. Ascl1 has also been reported to induce high efficiency of in vivo astrocyte-to-neuron conversion in the midbrain (Liu et al, 2015), suggesting that Ascl1 might share certain common properties with NeuroD1. Since long-term survival of converted neurons is essential to their integration into local neuronal circuitry in order to have a role in functional repair, future studies on clinical translation must pay much attention to the total number of newly generated neurons that can survive for years to have effective therapies.…”

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

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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Section: Environmental Cues To Impact Neuronal Conversion In Additionsupporting

confidence: 69%

Section: Neurod1 Reprograms Reactive Astrocytes Into Neurons In the Imentioning

confidence: 99%

Section: Distinct Functions Of Neurod1 During Neuronal Conversionmentioning

confidence: 99%

Section: Distinct Functions Of Neurod1 During Neuronal Conversionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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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Changing Fate: Reprogramming Cells via Engineered Nanoscale Delivery Materials

Dehnavi¹,

Zadeh

Harvey

et al. 2022

Advanced Materials

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The incorporation of nanotechnology in regenerative medicine is at the nexus of fundamental innovations and early‐stage breakthroughs, enabling exciting biomedical advances. One of the most exciting recent developments is the use of nanoscale constructs to influence the fate of cells, which are the basic building blocks of healthy function. Appropriate cell types can be effectively manipulated by direct cell reprogramming; a robust technique to manipulate cellular function and fate, underpinning burgeoning advances in drug delivery systems, regenerative medicine, and disease remodeling. Individual transcription factors, or combinations thereof, can be introduced into cells using both viral and nonviral delivery systems. Existing approaches have inherent limitations. Viral‐based tools include issues of viral integration into the genome of the cells, the propensity for uncontrollable silencing, reduced copy potential and cell specificity, and neutralization via the immune response. Current nonviral cell reprogramming tools generally suffer from inferior expression efficiency. Nanomaterials are increasingly being explored to address these challenges and improve the efficacy of both viral and nonviral delivery because of their unique properties such as small size and high surface area. This review presents the state‐of‐the‐art research in cell reprogramming, focused on recent breakthroughs in the deployment of nanomaterials as cell reprogramming delivery tools.

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In vivo glia‐to‐neuron conversion: pitfalls and solutions

Wang

Zhang

2022

Developmental Neurobiology

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Neuron loss and disruption of neural circuits are associated with many neurological conditions. A key question is how to rebuild neural circuits for functional improvements. In vivo glia‐to‐neuron (GtN) conversion emerges as a potential solution for regeneration‐based therapeutics. This approach takes advantage of the regenerative ability of resident glial cells to produce new neurons through cell fate reprogramming. Significant progress has been made over the years in this emerging field. However, inappropriate analysis often leads to misleading conclusions that create confusion and hype. In this perspective, we point out the most salient pitfalls associated with some recent studies and provide solutions to prevent them in the future. The goal is to foster healthy development of this promising field and lay a solid cellular foundation for future regeneration‐based medicine.

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Differential neuronal reprogramming induced by NeuroD1 from astrocytes in grey matter versus white matter

Cited by 58 publications

References 45 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

Changing Fate: Reprogramming Cells via Engineered Nanoscale Delivery Materials

In vivo glia‐to‐neuron conversion: pitfalls and solutions

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