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.
Cell. 2021 Oct 14;184(21):5465-5481.e16. doi: 10.1016/j.cell.2021.09.005. Epub 2021 Sep 27.
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.
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。
Gene Ther. 2023-12
Stem Cell Reports. 2017-5-11
Pharmacol Rev. 2025-6-26
Neural Regen Res. 2026-4-1
Cancer Biol Med. 2021-3-23
Mol Neurodegener. 2020-10-21
Neural Regen Res. 2021-4
Front Cell Neurosci. 2020-4-24