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在体追踪重新审视星形胶质细胞向神经元的转化。

Revisiting astrocyte to neuron conversion with lineage tracing in vivo.

机构信息

Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

出版信息

Cell. 2021 Oct 14;184(21):5465-5481.e16. doi: 10.1016/j.cell.2021.09.005. Epub 2021 Sep 27.


DOI:10.1016/j.cell.2021.09.005
PMID:34582787
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8526404/
Abstract

In vivo cell fate conversions have emerged as potential regeneration-based therapeutics for injury and disease. Recent studies reported that ectopic expression or knockdown of certain factors can convert resident astrocytes into functional neurons with high efficiency, region specificity, and precise connectivity. However, using stringent lineage tracing in the mouse brain, we show that the presumed astrocyte-converted neurons are actually endogenous neurons. AAV-mediated co-expression of NEUROD1 and a reporter specifically and efficiently induces reporter-labeled neurons. However, these neurons cannot be traced retrospectively to quiescent or reactive astrocytes using lineage-mapping strategies. Instead, through a retrograde labeling approach, our results reveal that endogenous neurons are the source for these viral-reporter-labeled neurons. Similarly, despite efficient knockdown of PTBP1 in vivo, genetically traced resident astrocytes were not converted into neurons. Together, our results highlight the requirement of lineage-tracing strategies, which should be broadly applied to studies of cell fate conversions in vivo.

摘要

体内细胞命运转变已成为治疗损伤和疾病的有潜力的基于再生的治疗方法。最近的研究报告称,异位表达或敲低某些因子可以高效、区域特异性和精确连接地将固有星形胶质细胞转化为功能性神经元。然而,我们通过在小鼠大脑中使用严格的谱系追踪表明,假定的星形胶质细胞转化神经元实际上是内源性神经元。AAV 介导的 NEUROD1 和报告基因的共表达特异性和高效地诱导报告基因标记的神经元。然而,这些神经元不能通过谱系追踪策略回溯到静止或反应性星形胶质细胞。相反,通过逆行标记方法,我们的结果表明,内源性神经元是这些病毒报告基因标记神经元的来源。同样,尽管体内 PTBP1 的有效敲低,但遗传追踪的固有星形胶质细胞并未转化为神经元。总之,我们的结果强调了谱系追踪策略的必要性,该策略应广泛应用于体内细胞命运转变的研究。

相似文献

[1]
Revisiting astrocyte to neuron conversion with lineage tracing in vivo.

Cell. 2021-10-14

[2]
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[3]
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[4]
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[6]
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[7]
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[8]
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[9]
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引用本文的文献

[1]
Development of a Lentiviral Reporter System for In Vitro Reprogramming of Astrocytes to Neuronal Precursors.

Biology (Basel). 2025-7-5

[2]
Neurons derived from NeuroD1-expressing astrocytes transition through transit-amplifying intermediates but lack functional maturity.

Sci Adv. 2025-7-25

[3]
Ptbp1 Knockdown in Glial Cells Promotes Motor and Sensory Function Recovery After Peripheral Nerve Injury.

CNS Neurosci Ther. 2025-7

[4]
Cell and tissue reprogramming: Unlocking a new era in medical drug discovery.

Pharmacol Rev. 2025-6-26

[5]
Ptbp1 is not required for retinal neurogenesis and cell fate specification.

bioRxiv. 2025-7-3

[6]
Stem cell repair strategies for epilepsy.

Neural Regen Res. 2026-4-1

[7]
PTBP1 Depletion in Mature Astrocytes Reveals Distinct Splicing Alterations Without Neuronal Features.

bioRxiv. 2025-6-3

[8]
To recruit or to graft? Comparing the recruitment of resident non-neuronal cells by lineage reprogramming with engraftment of stem cell-derived neurons for neuronal replacement therapies.

Front Neurosci. 2025-5-21

[9]
GADD45G operates as a pathological sensor orchestrating reactive gliosis and neurodegeneration.

Neuron. 2025-7-9

[10]
Transcription Factor-Based Gene Therapy Enables Functional Repair of Rat Following Chronic Ischemic Stroke.

CNS Neurosci Ther. 2025-5

本文引用的文献

[1]
Transcription factor-based gene therapy to treat glioblastoma through direct neuronal conversion.

Cancer Biol Med. 2021-3-23

[2]
In vivo reprogramming of NG2 glia enables adult neurogenesis and functional recovery following spinal cord injury.

Cell Stem Cell. 2021-5-6

[3]
Disease Modeling with Human Neurons Reveals LMNB1 Dysregulation Underlying DYT1 Dystonia.

J Neurosci. 2021-3-3

[4]
Aging-relevant human basal forebrain cholinergic neurons as a cell model for Alzheimer's disease.

Mol Neurodegener. 2020-10-21

[5]
Lineage tracing of direct astrocyte-to-neuron conversion in the mouse cortex.

Neural Regen Res. 2021-4

[6]
Selective Neuronal Vulnerability in Alzheimer's Disease: A Network-Based Analysis.

Neuron. 2020-6-29

[7]
Reversing a model of Parkinson's disease with in situ converted nigral neurons.

Nature. 2020-6-24

[8]
Regeneration Through Cell Fate Reprogramming for Neural Repair.

Front Cell Neurosci. 2020-4-24

[9]
Glia-to-Neuron Conversion by CRISPR-CasRx Alleviates Symptoms of Neurological Disease in Mice.

Cell. 2020-4-30

[10]
Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington's disease.

Nat Commun. 2020-2-27

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