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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Veröffentlicht in:	Cell Jg. 184; H. 21; S. 5465
Hauptverfasser:	Wang, Lei-Lei, Serrano, Carolina, Zhong, Xiaoling, Ma, Shuaipeng, Zou, Yuhua, Zhang, Chun-Li
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States 14.10.2021
Schlagworte:	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
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Zusammenfassung:	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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4172 1097-4172
DOI:	10.1016/j.cell.2021.09.005