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MicroRNA-Mediated In Vitro and In Vivo Direct Conversion of Astrocytes to Neuroblasts.

ABSTRACT: The conversion of astrocytes to neuroblasts holds great promise for treatment of neurodegenerative and traumatic brain diseases.Here we have shown that adult human astrocytes could be reprogrammed to neuroblasts by miR-302/367, both in vivo and in vitro. However, the reprogramming of adult mouse astrocytes to neuroblasts required valproic acid (VPA), a histone deacetylase inhibitor. Following induction of astrocytes toward neurons the expression of pluripotency markers were not detected, which suggested direct cell conversion. We did not observed tumor formation during two months follow up.These results show that neuroblasts can be generated directly from adult human and mouse astrocytes by miR-302/367-driven induction. This approach seems promising for converting glial scar cells into neuroblasts in a wide range of neurological diseases.

SUBMITTER: Ghasemi-Kasman M

PROVIDER: S-EPMC4451260 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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MicroRNA-Mediated In Vitro and In Vivo Direct Conversion of Astrocytes to Neuroblasts.

Ghasemi-Kasman Maryam M Hajikaram Maryam M Baharvand Hossein H Javan Mohammad M

PloS one 20150601 6

<h4>Background</h4>The conversion of astrocytes to neuroblasts holds great promise for treatment of neurodegenerative and traumatic brain diseases.<h4>Methodology and principal findings</h4>Here we have shown that adult human astrocytes could be reprogrammed to neuroblasts by miR-302/367, both in vivo and in vitro. However, the reprogramming of adult mouse astrocytes to neuroblasts required valproic acid (VPA), a histone deacetylase inhibitor. Following induction of astrocytes toward neurons the ...[more]

PMID: 26030913

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Project description:BackgroundReprogramming resident glial cells to convert them into neurons in vivo represents a potential therapeutic strategy that could replenish lost neurons, repair damaged neural circuits, and restore function. AAV (adeno-associated virus)-based expression systems are powerful tools for in vivo gene delivery in glia-to-neuron reprogramming, however, recent studies show that AAV-based gene delivery of Neurod1 into the mouse brain can cause severe leaky expression into endogenous neurons leading to misinterpretation of glia-to-neuron conversion.MethodsAAV-based delivery systems were modified for improved in vivo delivery of Neurod1, Math5, Ascl1, and Neurog2 in the adult mouse retina and brain. To examine whether bona fide glia-to-neuron conversion occurs, stringent fate mapping experiments were performed to trace the lineage of glial cells.FindingsThe neuronal leakage is prevalent after AAV-GFAP-mediated delivery of Neurod1, Math5, Ascl1, and Neurog2. The transgene-dependent leakage cannot be corrected after lowering the AAV doses, using alterative AAV serotypes or injection routes. Importantly, we report the development of two new AAV-based tools that can significantly reduce neuronal leakage. Using the new AAV-based tools, we provide evidence that Neurod1 gene transfer fails to convert lineage traced glial cells into neurons.InterpretationStringent fate mapping techniques independently of an AAV-based expression system are the golden standard for tracing the fate of glia cells during neuronal reprogramming. The newly developed AAV-based systems are invaluable tools for glia-to-neuron reprogramming in vivo.FundingThe work in Chen lab was supported by National Institutes of Health (NIH) grants R01 EY024986 and R01 EY028921, an unrestricted challenge grant from Research to Prevent Blindness, the New York Eye and Ear Infirmary Foundation, and The Harold W. McGraw, Jr. Family Foundation for Vision Research. The work in Zhang lab was supported by NIH (R01 NS127375 and R01 NS117065) and The Decherd Foundation.

Dataset Information

MicroRNA-Mediated In Vitro and In Vivo Direct Conversion of Astrocytes to Neuroblasts.

Publications

MicroRNA-Mediated In Vitro and In Vivo Direct Conversion of Astrocytes to Neuroblasts.

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