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Front Bioeng Biotechnol. 2018 Nov 21;6:173. doi: 10.3389/fbioe.2018.00173. eCollection 2018.

Transdifferentiating Astrocytes Into Neurons Using ASCL1 Functionalized With a Novel Intracellular Protein Delivery Technology.

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Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
Biomedical Engineering Program, University of Victoria, Victoria, BC, Canada.
Biology Program, University of Victoria, Victoria, BC, Canada.
Biochemistry Program, Bates College, Lewiston, ME, United States.
Mechanical Engineering, Faculty of Engineering, University of Victoria, Victoria, BC, Canada.
Center for Biomedical Research, Faculty of Engineering, University of Victoria, Victoria, BC, Canada.
International Collaboration for Repair Discovery, University of British Columbia, Vancouver, BC, Canada.


Cellular transdifferentiation changes mature cells from one phenotype into another by altering their gene expression patterns. Manipulating expression of transcription factors, proteins that bind to DNA promoter regions, regulates the levels of key developmental genes. Viral delivery of transcription factors can efficiently reprogram somatic cells, but this method possesses undesirable side effects, including mutations leading to oncogenesis. Using protein transduction domains (PTDs) fused to transcription factors to deliver exogenous transcription factors serves as an alternative strategy that avoids the issues associated with DNA integration into the host genome. However, lysosomal degradation and inefficient nuclear localization pose significant barriers when performing PTD-mediated reprogramming. Here, we investigate a novel PTD by placing a secretion signal sequence next to a cleavage inhibition sequence at the end of the target transcription factor-achaete scute homolog 1 (ASCL1), a powerful regulator of neurogenesis, resulting in superior stability and nuclear localization. A fusion protein consisting of the amino acid sequence of ASCL1 transcription factor with this novel PTD added can transdifferentiate cerebral cortex astrocytes into neurons. Additionally, we show that the synergistic action of certain small molecules improves the efficiency of the transdifferentiation process. This study serves as the first step toward developing a clinically relevant in vivo transdifferentiation strategy for converting astrocytes into neurons.


drug delivery; neuroscience; reprogramming; small molecules; transcription factors

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