Functions of reactive astrocytes and regulation of astrogliosis after spinal cord injury.

摘要

Reactive astrocytes are prominent in the response to spinal cord injury, but their functions are poorly understood. I used two transgenic mouse models to examine the roles of reactive astrocytes after spinal cord injury (SCI). In my first model, I selectively ablated reactive astrocytes after crush SCI. Mice expressing a GFAP-HSV-TK transgene were given a moderate SCI and treated with the antiviral agent ganciclovir (GCV) to ablate dividing, reactive, transgene-expressing astrocytes in the immediate vicinity of the SCI. I found that after injury, animals with reactive astrocyte ablation exhibited increases in inflammatory responses, demyelination, and lesion size compared to animals without reactive astrocyte ablation. I also found impairments in functional recovery. Control animals recovered locomotor ability and motor coordination to near pre-injury levels. Animals with reactive astrocyte ablation did not recover locomotion or motor coordination by day 14 after SCI. From this study I conclude that reactive astrocytes have essential protective functions after SCI.; In my second model, I wanted to understand the effect of altering the signaling pathways involved in regulating astrocyte reactivity. My goal in these experiments was to maintain the presence of astrocytes after SCI, but attenuate their reactivity. I focused on the STAT3 protein, which has been proposed to be involved in regulating astrocyte reactivity. The Cre-loxP system was used to delete STAT3 selectively in astrocytes. Astrocytes deficient in STAT3 signaling exhibited reduced expression of GFAP and vimentin, decreased hypertrophy, decreased proliferation, and disorganized glial scar formation after SCI. Taken together, I conclude that astrocyte reactivity has been successfully attenuated astrocyte reactivity by deleting STAT3 from astrocytes, and that STAT3 is an important regulator of astrocyte reactivity after SCI.; In addition, I wanted to know the effect of attenuating astrocyte reactivity on certain aspects of functional recovery and tissue response after SCI. My results show that moderate crush injuries in STAT3 deficient mice caused increases in lesion size, inflammatory response, demyelination, and reduced recovery of locomotor function. These results show that astrocytes with attenuated reactivity do not promote tissue repair or functional recovery as well as fully reactive astrocytes.