Revisiting astrocyte to neuron conversion with lineage tracing in vivo
- PMID: 34582787
- PMCID: PMC8526404
- DOI: 10.1016/j.cell.2021.09.005
Revisiting astrocyte to neuron conversion with lineage tracing in vivo
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.
Keywords: AAV; CRISPR-CasRx; DLX2; NEUROD1; PAX6; PTBP1; astrocyte-to-neuron conversion; in vivo reprogramming; lineage tracing; shRNA.
Copyright © 2021 Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of interests The authors declare no competing interests.
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Comment in
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cAAVe phaenomena: Beware of appearances!Cell. 2021 Oct 14;184(21):5303-5305. doi: 10.1016/j.cell.2021.09.027. Cell. 2021. PMID: 34653366
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In vivo confusion over in vivo conversion.Mol Ther. 2021 Nov 3;29(11):3097-3098. doi: 10.1016/j.ymthe.2021.10.017. Epub 2021 Oct 25. Mol Ther. 2021. PMID: 34699780 Free PMC article. No abstract available.
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Reply to In vivo confusion over in vivo conversion.Mol Ther. 2022 Mar 2;30(3):986-987. doi: 10.1016/j.ymthe.2022.01.027. Epub 2022 Feb 1. Mol Ther. 2022. PMID: 35108505 Free PMC article. No abstract available.
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Limited astrocyte-to-neuron conversion in the mouse brain using NeuroD1 overexpression.Mol Ther. 2022 Mar 2;30(3):982-986. doi: 10.1016/j.ymthe.2022.01.028. Epub 2022 Feb 4. Mol Ther. 2022. PMID: 35123657 Free PMC article. No abstract available.
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References
-
- Barker RA, Gotz M, and Parmar M (2018). New approaches for brain repair-from rescue to reprogramming. Nature 557, 329–334. - PubMed
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