Revisiting astrocyte to neuron conversion with lineage tracing in vivo

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 precis...

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Bibliographic Details
Published in:Cell Vol. 184; no. 21; p. 5465
Main Authors: Wang, Lei-Lei, Serrano, Carolina, Zhong, Xiaoling, Ma, Shuaipeng, Zou, Yuhua, Zhang, Chun-Li
Format: Journal Article
Language:English
Published: United States 14.10.2021
Subjects:
Animals
Astrocytes - cytology
Astrocytes - metabolism
Basic Helix-Loop-Helix Transcription Factors - metabolism
Brain - pathology
Brain Injuries - pathology
Cell Differentiation
Cell Line, Tumor
Cell Lineage
Cellular Reprogramming
Dependovirus - metabolism
Down-Regulation
Gene Expression Regulation
Genes, Reporter
Glial Fibrillary Acidic Protein - genetics
Heterogeneous-Nuclear Ribonucleoproteins - metabolism
Homeodomain Proteins - metabolism
Humans
Integrases - metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neurons - cytology
Neurons - metabolism
Polypyrimidine Tract-Binding Protein - metabolism
Promoter Regions, Genetic - genetics
Transcription Factors - metabolism
NEUROD1
in vivo reprogramming
PTBP1
DLX2
astrocyte-to-neuron conversion
shRNA
AAV
PAX6
lineage tracing
CRISPR-CasRx
ISSN:1097-4172, 1097-4172
Online Access:Get more information
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Summary: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.
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2021.09.005