The origins and dynamic changes of C3- and S100A10-positive reactive astrocytes after spinal cord injury

Abstract

Accaumulating studies focus on the effects of C3-positive A1-like phenotypes and S100A10-positive A2-like phenotypes of reactive astrocytes on spinal cord injury (SCI), however the origins and dynamic changes of C3- and S100A10-positive reactive astrocytes after SCI remain poorly understood. Through transgenic mice and lineage tracing, we aimed to determine the origins of C3- and S100A10-positive reactive astrocytes. Meanwhile, the distribution and dynamic changes in C3- and S100A10-positive reactive astrocytes were also detected in juvenile and adult SCI mice models and cultured astrocytes. Combing with bulk RNA sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq) and bioinformatic analysis, we further explored the dynamic transcripts changes of C3- and S100A10-positive reactive astrocytes after SCI. We confirmed that resident astrocytes produced both C3- and S100A10-positive reactive astrocytes, whereas ependymal cells regenerated only S100A10-positive reactive astrocytes in lesion area. Importantly, C3-positive reactive astrocytes were predominantly activated in adult SCI mice, while S100A10-positive reactive astrocytes were hyperactivated in juvenile mice. Furthermore, we observed that C3- and S100A10-positive reactive astrocytes had a dynamic transformation process at different time in vitro and vivo, and a majority of intermediate states of C3- and S100A10-positive reactive astrocytes were found during transformation. RNA-seq and scRNA-seq results further confirmed that the transcripts of C3-positive reactive astrocytes and their lipid toxicity were gradually increased with time and age. In contrast, S100A10-positive reactive astrocytes transcripts increased at early time and then gradually decreased after SCI. Our results provide insight into the origins and dynamic changes of C3- and S100A10-positive reactive astrocytes after SCI, which would be valuable resources to further target C3- and S100A10-positive reactive astrocytes after SCI.

The Impact of Treadmill Training on Tissue Integrity, Axon Growth, and Astrocyte Modulation

“…Similar results were obtained in the study by Ying et al, 2022, where it was found that training on a water treadmill promotes the development of S100A10 + -reactive astrocytes [25]. This same study also demonstrated a reduction in pro-inflammatory astrocytes (the second line of astrocytes, known as resident cells [55][56][57][58]) expressing the C3 protein. The existing discrepancy between the observed levels of C3 mRNA in our work and the C3 protein in Ying et al, 2022 [25] may be due to differential regulation of translation, post-translational modifications, protein half-life, and antibody epitope availability.…”

“…The reduction in the number of GFAP + /ALDH1L1 + -astrocytes in the group with controlled training in our study also supports the hypothesis of a positive effect of physical exercise on the state of the glial scar. Recent studies have demonstrated that the microenvironment of the glial scar gradually transforms, inhibiting regeneration as the scar matures, and the function of astrocytes progressively shifts from stimulating to inhibiting axonal regeneration [55,56]. Limiting secondary damage caused by inflammation may be a specific function of astrocytes, precursors of ependymal cells (one of the three astrocyte lineages identified in SCI [55][56][57][58]), including S100A10 + -reactive astrocytes.…”

“…Recent studies have demonstrated that the microenvironment of the glial scar gradually transforms, inhibiting regeneration as the scar matures, and the function of astrocytes progressively shifts from stimulating to inhibiting axonal regeneration [55,56]. Limiting secondary damage caused by inflammation may be a specific function of astrocytes, precursors of ependymal cells (one of the three astrocyte lineages identified in SCI [55][56][57][58]), including S100A10 + -reactive astrocytes. An increase in these cells after training indicates the induction of morphological changes and proliferation of astrocytes, aimed at forming neuroprotective phenotypes.…”