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  • antioxidants Ependymal cell derived astrocytes are located a

    2018-10-23

    Ependymal cell-derived astrocytes are located at the core of the lesion site, while resident astrocytes proliferate and are recruited at the border of the lesion site after spinal cord injury (Barnabe-Heider and Frisen, 2008; Burda and Sofroniew, 2014). It was demonstrated that ageing changes the astrocyte physiology and the sensitivity to oxidative stress, and age-related astrocytic changes in the central nervous system results in reduced VEGF and FGF-2 signaling, which in turn limits neural stem cell and progenitor cell maintenance and contributes to decreased neural stem cell potential (Bernal and Peterson, 2011; Lin et al., 2007). We observed that juvenile ependymal cells are not recruited to the lesion site in vivo after mild SCI in juvenile mice. In parallel, we also observed that the sealing of the lesion is more efficient in juvenile compared to adult mice when we performed SCI of the same severity. This suggests that juvenile resident astrocytes may contribute to sealing the lesion more efficiently than during adulthood. This may lead to a more pro-regenerative environment and the activation, recruitment and differentiation of ependymal cells into astrocytes is not required in juvenile mice as much as during adulthood following SCI. However, in case of severe SCI, juvenile ependymal cells migrate towards the core of the lesion site, showing the same phenotype that was previously described in response to both mild and severe SCI in adult mice (Barnabe-Heider et al., 2010; Sabelstrom et al., 2013). Importantly, one previous study showed that blocking the recruitment and proliferation of adult ependymal cells results in development of large cysts at the lesion sites, implying that ependymal cell progeny functions as a scaffold within the scar to restrict secondary enlargement of the lesion after the initial insult (Sabelstrom et al., 2013). We showed here that when the antioxidants is blocked in juvenile ependymal cells, no cysts develop in the mouse spinal cord after severe SCI. This supports the idea that juvenile ependymal cells play a secondary role in the sealing and enlargement of the lesion site as other glial cell populations are already responding to the lesion. Moreover, this sheds light on the importance of the environment to efficiently recruit endogenous stem cells upon SCI. Altogether, our data show that despite the presence of ependymal cell stem cell potential in both juvenile and adult spinal cords, they react in vivo as backup participants in the response to SCI in juvenile mice, i.e., only when the injury is too severe to be sufficiently sealed by the other resident glial cells, such as astrocytes. This highlights that efficient modulation of ependymal cells and the glial scar response both have to be considered in the therapeutic context. Besides resident astrocytes and ependymal cells, other glial cell types, including microglia, blood-derived macrophages and stromal cells, also have a major role in glial scar formation after SCI and influence antioxidants the reactivity of resident astrocytes (Goritz et al., 2011; Jin and Yamashita, 2016; Schwartz, 2010). We investigated whether these mechanisms would also influence the migration and activation of ependymal cells in mild and severe SCI in juvenile and adulthood. During glial scar formation, glial cells influence each other response and recruitment to the lesion site (Stenudd et al., 2015). In juvenile mice, we report that mild SCI results in reduced activation and recruitment of microglia and blood-derived macrophages to the lesion site compared to their response following severe SCI. Also, the microglia/blood-derived macrophages activation and recruitment reaches the extent observed in adulthood only when a severe injury is performed in juvenile mice. Therefore, we suggest that juvenile reactive astrocytes are more pro-regenerative than in the adult. Pericytes are the major cell type forming the fibrotic cap filling the lesion site after SCI (Goritz et al., 2011). We observed that in juvenile mice the stromal cap is reduced in size compared to adult spinal cords when the same kind of injury is performed. The differences among several cells types involved in self-repair reveal that the regenerative and recovery potential of the spinal cord decreases not only during development but also during ageing. That could be due to the age-dependent transcriptome changes in terms of inflammation or metabolism (Saunders et al., 2014; Noor et al., 2011). Notably, there is clinical evidence that people who have sustained SCI during pediatric rather than adult ages enjoy better overall health and functional recovery as well as reduced pain (Ma et al., 2016). Consist with this, our data on the formation of the glial and stromal scars suggest that juvenile spinal cords have a more pronounced potential for self-repair than adult cords, which could be highly relevant to the development of optimal individual SCI therapies.