Silencing neuroinflammatory reactive astrocyte activating factors ameliorates disease outcomes in perinatal white matter injury

Abstract

The role of reactive astrocytes in perinatal white matter injury (WMI) is unclear. In a mouse model of WMI, we provide evidence that impairing the formation of a C3-expressing neuroinflammatory reactive astrocyte sub-state rescues myelination and behavioral deficits. We further demonstrate the presence of C3-expressing reactive astrocytes in human WMI. Our data point to these cells as putative drivers of myelination failure in WMI and a potentially promising therapeutic target.

Perinatal Brain Injury Triggers Niche-Specific Changes to Cellular Biogeography

“…This is consistent with previous work showing that there is an increase in the number of C3 -expressing reactive astrocytes in the corpus callosum following acute perinatal WMI. 28,29…”

“…This is consistent with previous work showing that there is an increase in the number of C3-expressing reactive astrocytes in the corpus callosum following acute perinatal WMI. 28,29 In the cortex of HX mice, we identified a significant increase in the abundance in Endo-1 cells, the most abundant subpopulation of endothelial cells (82% increase, p = 0.015, Figure 2I), suggestive of vascular remodeling. Lastly, we observed a significant increase in the proportion of a large population of excitatory neurons in layer II-III (18% increase, p = 0.019), and a significant decrease in a small population of excitatory neurons in layers I-III (54% reduction, p = 0.049, Figure 2K), indicating a change in the cell type composition of upper layer excitatory neurons with an overall increase in excitatory neurons.…”