Astrocytes, reactive gliosis and CNS regeneration

Abstract

The regenerative capacity in the adult central nervous system (CNS) is very limited, and the glial cells have been implicated in the inhibition of CNS regeneration. In essentially all CNS pathologies, astrocytes are activated and this process is known as reactive gliosis. Upregulation of intermediate filament proteins GFAP and vimentin and hypertrophy of cellular processes are the hallmarks of reactive gliosis. The focus of this thesis were astrocytes, in particular reactive astrocytes, and their role in regeneration in the adult CNS.Loss of GFAP, seen in many high grade astrocytomas, has been suspected to constitute a step in tumor development. By induction of astrocytomas in GFAP-/- mice in vivo, no difference in tumor development or progression was seen, suggesting that loss of GFAP seen in tumor cells rather reflects the undifferentiated state of these cells. Response to electrically induced injury of brain cortex and the hippocampus was assessed in knock-out mice depleted of neuron-derived PDGF-B, a possible modulator of reactive gliosis. We concluded that neuron-derived PDGF-B is not required for injury-triggered reactive gliosis, activation of microglia or neovascularization.GFAP-/-Vim-/- mice were previously reported to display less prominent post-traumatic glial scars. This animal model was used to study the integration of retinal grafts in the adult mouse retina. In contrast to wild-type, the GFAP-/-Vim-/- retinas provided a highly permissive environment for retinal transplants. Grafted cells migrated extensively into the host retina, differentiated into neurons and stayed integrated in the GFAP-/-Vim-/- retinas by six months after transplantation.To assess the role of reactive astrocytes in neuroprotection and regeneration after CNS trauma, GFAP-/-Vim-/- mice were subjected to a lesion partially denervating the dentate gyrus of the hippocampus. At an early stage after the lesion, GFAP-/-Vim-/- astrocytes provided less neuroprotection, but at a later time-point the same mice showed vastly improved regeneration of neuronal synapses as well as increased number of newborn neurons. Cell proliferation and neurogenesis in the hippocampus was also studied in healthy old GFAP-/-Vim-/- and wild-type mice, in which aging triggers mild and progressing reactive gliosis. Compared to wild-type, GFAP-/-Vim-/- mice showed increased cell proliferation and neurogenesis in the dentate gyrus of the hippocampus. This suggests that modulation of astrocyte reactivity increases neurogenesis even in the absence of a trauma or other challenge.