Influence of white matter injury on gray matter reactive gliosis upon stab wound in the adult murine cerebral cortex

Abstract

Traumatic brain injury frequently affects the cerebral cortex, yet little is known about the differential effects that occur if only the gray matter (GM) is damaged or if the injury also involves the white matter (WM). To tackle this important question and directly compare similarities and differences in reactive gliosis, we performed stab wound injury affecting GM and WM (GM+) and one restricted to the GM (GM-) in the adult murine cerebral cortex. First, we examined glial reactivity in the regions affected (WM and GM) and determined the influence of WM injury on reactive gliosis in the GM comparing the same area in the two injury paradigms. In the GM+ injury microglia proliferation is increased in the WM compared with GM, while proliferating astrocytes are more abundant in the GM than in the WM. Interestingly, WM lesion exerted a strong influence on the proliferation of the GM glial cells that was most pronounced at early stages, 3 days post lesion. While astrocyte proliferation was increased, NG2 glia proliferation was decreased in the GM+ compared with GM- lesion condition. Importantly, these differences were not observed when a lesion of the same size affected only the GM. Unbiased proteomic analyses further corroborate our findings in support of a profound difference in GM reactivity when WM is also injured and revealed MIF as a key regulator of NG2 glia proliferation.

Filling the Gaps – A Call for Comprehensive Analysis of Extracellular Matrix of the Glial Scar in Region- and Injury-Specific Contexts

“…Comparing previous proteomes obtained at the acute stages 3 and 5 dpi (Frik et al, 2018;Mattugini et al, 2018), we find scarrelated ECM proteins peak at 5 days. At this time, we find Ftl1/2 to be present on and around CD68+ macrophages, although it seems to only be a subset that is responsible for the Ftl1/2 secretion (Figure 2A).…”

“…These proteins could originate from the blood (Geyer et al, 2016). However, bioinformatic comparison from our previous publications with proteomes from the stab wound at 3 and 5 days after injury, hinted that this was unlikely (Frik et al, 2018;Mattugini et al, 2018). In these proteomes, blood proteins are highly abundant at 3 days after stab wound injury, but are instead reduced at 5 days.…”

Traumatic brain injury‐induced neuronal damage in the somatosensory cortex causes formation of rod‐shaped microglia that promote astrogliosis and persistent neuroinflammation

“…Notably, CD45 mRNA and protein were increased 7 dpi. CD45 is highly expressed by leukocytes and is commonly used as an indicator of leukocyte infiltration to the brain (Mattugini et al, ). While we did observe occasional monocyte infiltration after diffuse TBI, much of the CD45 protein was expressed by hypertrophied microglia ventral to rod microglial trains.…”

“…Notably, CD45 mRNA and protein were increased 7 dpi. CD45 is highly expressed by leukocytes and is commonly used as an indicator of leukocyte infiltration to the brain (Mattugini et al, 2018).…”

Proteomic changes in traumatic brain injury: experimental approaches

“…Mattugini et al [ 4 ▪▪ ] used a proteomics approach to examine differences in stab wound injury in the adult murine cerebral cortex. The focus of the study was to determine if damage resulting from injury to gray matter alone was different from gray matter extending into the underlying white matter 3 days post injury.…”