Journal
MOLECULAR NEURODEGENERATION
Volume 11, Issue -, Pages -Publisher
BIOMED CENTRAL LTD
DOI: 10.1186/s13024-016-0133-0
Keywords
Spinal cord injury; Astrocytes; Astrogliosis; Transdifferentiation; Cell specific transcriptomic
Categories
Funding
- Spanish Government, Plan Nacional de I + D + I
- ISCIII- Subdireccion General de Evaluacion y Fomento de la investigacion [PI10/00709]
- Government of the Basque Country grant (Proyectos de Investigacion Sanitaria and Fondo Comun de Cooperacion Aquitania-Euskadi)
- French Government
- ANR-FNS grant
- GliALS [ANR-14-CE36-0009-01]
- Agence Nationale de la Recherche (ANR) [ANR-14-CE36-0009] Funding Source: Agence Nationale de la Recherche (ANR)
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Background: Neurons have intrinsic capability to regenerate after lesion, though not spontaneously. Spinal cord injury (SCI) causes permanent neurological impairments partly due to formation of a glial scar that is composed of astrocytes and microglia. Astrocytes play both beneficial and detrimental roles on axonal re-growth, however, their precise role after SCI is currently under debate. Methods: We analyzed molecular changes in astrocytes at multiple stages after two SCI severities using cell-specific transcriptomic analyses. Results: We demonstrate that astrocyte response after injury depends on both time after injury and lesion severity. We then establish that injury induces an autologous astroglial transdifferentiation where over 10 % of astrocytes express classical neuronal progenitor markers including beta III-tubulin and doublecortin with typical immature neuronal morphology. Lineage tracing confirmed that the origin of these astrocytes is resident mature, rather than newly formed astrocytes. Astrocyte-derived neuronal progenitors subsequently express GABAergic, but not glutamatergic-specific markers. Furthermore, we have identified the neural stem cell marker fibroblast growth factor receptor 4 (Fgfr4) as a potential autologous modulator of astrocytic transdifferentiation following SCI. Finally, we establish that astroglial transdifferentiation into neuronal progenitors starts as early as 72 h and continues to a lower degrees up to 6 weeks post-lesion. Conclusion: We thus demonstrate for the first time autologous injury-induced astroglial conversion towards neuronal lineage that may represent a therapeutic strategy to replace neuronal loss and improve functional outcomes after central nervous system injury.
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