Regional heterogeneity in astrocyte responses following contusive spinal cord injury in mice

Abstract

Astrocytes and their precursors respond to spinal cord injury (SCI) by proliferating, migrating, and altering phenotype. This contributes to glial scar formation at the lesion border and gliosis in spared gray and white matter. The present study was undertaken to evaluate astrocyte changes over time and determine when and where interventions might be targeted to alter the astrocyte response. Bromodeoxyuridine (BrdU) was administered to mice three days after SCI, and cells expressing BrdU and the astrocyte marker, glial fibrillary acidic protein (GFAP), were counted at 3, 7, and 49 days post injury (DPI). BrdU-labeled cells accumulated at the lesion border by 7 DPI and approximately half of these expressed GFAP. In spared white matter, the total number of BrdU+ cells decreased, while the percentage of BrdU+ cells expressing GFAP increased at 49 DPI. Phenotypic changes were examined using the progenitor marker, nestin, the radial glial marker, brain lipid binding protein (BLBP), and GFAP. Nestin was upregulated by 3 DPI and declined between 7 and 49 DPI in all regions, and GFAP increased and remained above naïve levels at all time points. BLBP increased early and remained high along the lesion border and spared white matter, but was expressed transiently by cells lining the central canal and in a unique population of small cells found within the lesion and in gray matter rostral and caudal to the border. The results demonstrate that the astrocyte response to SCI is regionally heterogeneous, and suggests astrocyte populations which could be targeted by interventions.

Delayed Applications of L1 and Chondroitinase ABC Promote Recovery after Spinal Cord Injury

“…Here we found no effect of delayed AAV-L1 application on GFAP expression by astrocytes at 15 weeks after SCI. A possible explanation for these differences is that delayed L1 overexpression after the third week after injury, in contrast to acute application, cannot influence astrocyte proliferation, which occurs mostly during the first week after injury (Lytle and Wrathall, 2007;White et al, 2010). In contrast to L1, Chase treatment was associated with a significantly lower level of GFAP expression, whereas treatment with both agents, AAV-L1, or Chase, led to reduction of NG2-positive glial cells.…”

Astrogliosis

“…The essentially nonoverlapping astrocyte domains found in healthy gray matter are more or less preserved in mild to moderate reactive astrogliosis in brain and spinal cord ( Fig. 2) Compact astroglial scars derive almost entirely from newly proliferated astrocytes with elongated shapes (Wanner et al 2013), whose cell processes overlap and intertwine extensively to form compact borders that surround and demarcate areas of tissue damage, necrosis, and inflammation after trauma, stroke, infection, autoimmune-triggered inflammatory infiltration, or neurodegenerative disease (Bush et al 1999;Faulkner et al 2004;Drogemuller et al 2008;Voskuhl et al 2009;White et al 2010;Wanner et al 2013). There may be several possible sources of newly divided scar-forming astrocytes including (1) mature astrocytes that reenter the cell cycle and proliferate (Bush et al 1999;Buffo et al 2008;Gadea et al 2008;Bardehle et al 2013), (2) NG2 progenitor cells in the local parenchyma (Magnus et al 2008), or (3) ependymal cell progenitors (Meletis et al 2008;Barnabe-Heider et al 2010).…”

The diversity and disparity of the glial scar

“…However, distinct reactive astrocyte populations have also been observed within the same CNS region. For example, in spinal cord glial scars, reactive astrocytes have been found to express differing levels of GFAP, nestin and brain lipid-binding protein (BLBP) 18 . Furthermore, only subsets of astrocytes were found to react to a cortical stab injury, either by polarization toward lesion sites or by proliferation 19 .…”