AAV Ablates Neurogenesis in the Adult Murine Hippocampus
| Autor: | Fred H. Gage, Christina K. Lim, Stacy Kim, Iryna Gallina, Ondrej Novak, Alexander Newberry, Cooper W Bloyd, Nolan Mac, Christian D Saavedra, J. Tiago Gonçalves, Matthew Shtrahman, Sarah L. Parylak, Stephen T. Johnston |
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| Rok vydání: | 2020 |
| Předmět: |
Central Nervous System
Male 0301 basic medicine Mouse hippocampus viruses Genetic enhancement Inbred C57BL neuroscience Mice Transduction (genetics) 0302 clinical medicine Neural Stem Cells dentate gyrus Biology (General) Neurons 0303 health sciences Cell Death General Neuroscience Neurogenesis Gene Therapy General Medicine Dependovirus Stem Cells and Regenerative Medicine gene therapy Neural stem cell 3. Good health Cell biology adult neurogenesis Medicine Stem Cell Research - Nonembryonic - Non-Human Development of treatments and therapeutic interventions Stem cell Immediate early gene Research Article Biotechnology Adult Cell type QH301-705.5 Science Genetic Vectors regenerative medicine adeno-associated virus (AAV) adeno-associated virus Biology General Biochemistry Genetics and Molecular Biology Viral vector 03 medical and health sciences stem cells Genetics Animals Humans neural progenitor cell mouse Cell Proliferation 030304 developmental biology Inflammation 5.2 Cellular and gene therapies General Immunology and Microbiology Dentate gyrus Neurosciences Genetic Therapy Stem Cell Research Mice Inbred C57BL 030104 developmental biology Biochemistry and Cell Biology 030217 neurology & neurosurgery Neuroscience |
| Zdroj: | eLife eLife, Vol 10 (2021) |
| DOI: | 10.1101/2020.01.18.911362 |
| Popis: | Recombinant adeno-associated virus (rAAV) has been widely used as a viral vector across mammalian biology and has been shown to be safe and effective in human gene therapy. We demonstrate that neural progenitor cells (NPCs) and immature dentate granule cells (DGCs) within the adult murine hippocampus are particularly sensitive to rAAV-induced cell death. Cell loss is dose dependent and nearly complete at experimentally relevant viral titers. rAAV-induced cell death is rapid and persistent, with loss of BrdU-labeled cells within 18 hours post-injection and no evidence of recovery of adult neurogenesis at 3 months post-injection. The remaining mature DGCs appear hyperactive 4 weeks post-injection based on immediate early gene expression, consistent with previous studies investigating the effects of attenuating adult neurogenesis. In vitro application of AAV or electroporation of AAV2 inverted terminal repeats (ITRs) is sufficient to induce cell death. Efficient transduction of the dentate gyrus (DG)—without ablating adult neurogenesis—can be achieved by injection of rAAV2-retro serotyped virus into CA3. rAAV2-retro results in efficient retrograde labeling of mature DGCs and permits in vivo 2-photon calcium imaging of dentate activity while leaving adult neurogenesis intact. These findings expand on recent reports implicating rAAV-linked toxicity in stem cells and other cell types and suggest that future work using rAAV as an experimental tool in the DG and as a gene therapy for diseases of the central nervous system (CNS) should be carefully evaluated. |
| Databáze: | OpenAIRE |
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