Injury-specific factors in the cerebrospinal fluid regulate astrocyte plasticity in the human brain

Abstract

The glial environment influences neurological disease progression, yet much of our knowledge still relies on preclinical animal studies, especially regarding astrocyte heterogeneity. In murine models of traumatic brain injury, beneficial functions of proliferating reactive astrocytes on disease outcome have been unraveled, but little is known regarding if and when they are present in human brain pathology. Here we examined a broad spectrum of pathologies with and without intracerebral hemorrhage and found a striking correlation between lesions involving blood–brain barrier rupture and astrocyte proliferation that was further corroborated in an assay probing for neural stem cell potential. Most importantly, proteomic analysis unraveled a crucial signaling pathway regulating this astrocyte plasticity with GALECTIN3 as a novel marker for proliferating astrocytes and the GALECTIN3-binding protein LGALS3BP as a functional hub mediating astrocyte proliferation and neurosphere formation. Taken together, this work identifies a therapeutically relevant astrocyte response and their molecular regulators in different pathologies affecting the human cerebral cortex.

Integrative single-cell analysis of neural stem/progenitor cells reveals epigenetically dysregulated interferon response in progressive multiple sclerosis

“…Recent work has demonstrated that astrocytes exhibit plasticity in injury situations. 41 Human pathologies which involved lesions and blood-brain barrier rupture were associated with a de-differentiation of astrocytes to replicating NSC/RG-like cells. 41 Furthermore, this has been previously validated in rodent models where epithelial injury allows for neural precursors to dedifferentiate into multipotent NSCs in the olfactory epithelium.…”

“…41 Human pathologies which involved lesions and blood-brain barrier rupture were associated with a de-differentiation of astrocytes to replicating NSC/RG-like cells. 41 Furthermore, this has been previously validated in rodent models where epithelial injury allows for neural precursors to dedifferentiate into multipotent NSCs in the olfactory epithelium. 104 Based on these studies, astrocytes in PMS may be undergoing (i) a de-differentiation (or de-maturation) process, where they begin to express cell cycle and early RG-like cell markers due to exposure of chronic inflammation, and a (ii) resurgence as non-neurogenic RG-like cells at the level of disease-associated, ectopic, non-canonical niches.…”

“…36,37 However, their capacity for neurogenesis and differentiation, as well as their presence outside of the main CNS germinal stem cell niches is much debated. 38,39 More recently, phenomena such as inflammation and injury support both de-maturation of neurons 40 and de-differentiation of astrocytes 41 into NSC/RG-like cell states. NSCs expressing glial markers and displaying features of senescence have also been identified near lesioned areas in post-mortem MS brain tissue.…”

Mapping dynamic molecular changes in hippocampal subregions after traumatic brain injury through spatial proteomics

“…Noteworthy are the region-specific abundance changes observed in proteins like fibronectin 1 (FN1), LGALS3BP, haptoglobin (HP), and MUG-1, which were exclusively overexpressed in the SM subregion at both TBI day 1 and day 7 post-TBI. Of these proteins, LGALS3BP is a key player in astrocyte proliferation and neurosphere formation [ 88 ], and MUG-1 was previously implicated in neutrophil degranulation [ 89 ]. As also evidenced by our pathway analysis, acute phase response signaling was also enriched in SM as compared to other sub-regions.…”