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A NeuroD1 AAV-Based Gene Therapy For Functional Brain Repair After Ischemic Injury Through In Vivo Astrocyte-To-Neuron Conversion

ABSTRACT: A NeuroD1 AAV-Based Gene Therapy For Functional Brain Repair After Ischemic Injury Through In Vivo Astrocyte-To-Neuron Conversion

PROVIDER: PRJNA560878 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10001352.fastq.gz	Fastqsanger.gz
	SRR10001353.fastq.gz	Fastqsanger.gz
	SRR10001354.fastq.gz	Fastqsanger.gz
	SRR10001355.fastq.gz	Fastqsanger.gz
	SRR10001356.fastq.gz	Fastqsanger.gz

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A NeuroD1 AAV-Based Gene Therapy For Functional Brain Repair After Ischemic Injury Through In Vivo Astrocyte-To-Neuron Conversion

Project description:NeuroD1-mediated in situ astrocyte-to-neuron conversion can regenerate a large number of functional new neurons after ischemic injury. RNA-sequencing was conducted to confirm neuronal recovery after cell conversion at the mRNA level.

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Transcriptional changes and microRNA expression profiles during NeuroD1-mediated astrocyte-to-neuron conversion

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A NeuroD1 AAV-Based Gene Therapy for Functional Brain Repair after Ischemic Injury through In Vivo Astrocyte-to-Neuron Conversion.

Project description: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 situ astrocyte-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 vivo cell conversion technology through NeuroD1-based gene therapy can regenerate a large number of functional new neurons to restore lost neuronal functions after injury.

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Intravenous NeuroD1 Gene Therapy Rescues Neurovascular Impairment After Ischemic Stroke

Project description:Intravenous NeuroD1 Gene Therapy Rescues Neurovascular Impairment After Ischemic Stroke

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Intravenous NeuroD1 Gene Therapy Rescues Neurovascular Impairment After Ischemic Stroke

Project description:Intravenous NeuroD1 Gene Therapy Rescues Neurovascular Impairment After Ischemic Stroke

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NeuroD1 reprograms chromatin and transcription factor landscapes to induce the neuronal program

Project description:Cell fate specification relies on the action of critical transcription factors that become available at distinct stages of embryonic development. One such factor is NeuroD1, which is essential for eliciting the neuronal development program and possesses the ability to reprogram other cell types into neurons. Given this capacity, it is important to understand its targets and the mechanism underlying neuronal specification. Here, we show that NeuroD1 directly binds regulatory elements of neuronal genes that are developmentally silenced by epigenetic mechanisms. This targeting is sufficient to initiate events that confer transcriptional competence, including reprogramming of transcription factor landscape, conversion of heterochromatin to euchromatin and increased chromatin accessibility, indicating potential pioneer factor ability of NeuroD1. The transcriptional induction of neuronal fate genes is maintained via epigenetic memory despite a transient NeuroD1 induction during neurogenesis. Our study not only reveals the NeuroD1-dependent gene regulatory program driving neurogenesis but also increases our understanding of how cell-fate specification during development involves a concerted action of transcription factors and epigenetic mechanisms. 1. Ectopic NeuroD1 was induced for 48 hours (+Dox) in ES cells for checking initiation of neuronal transcriptional program in comparison to uninduced condition (-Dox) 2. ChIP-seq was performed after 24 hours of NeuroD1 induction in ES cells.

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RNA-seq analysis of gene expression in cells during Ascl1 mediated astrocyte-to-neuron conversion.

Project description:We analyzed the transcriptomic changes in cells sorted from astrocyte-to-neuron conversion at different stages, identified the differentially expressed genes (DEGs), and functionally validated the critical DEGs.

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