Astrocyte Regulation of CNS Myelination

Demyelination of the central nervous system (CNS) is a primary pathology underlying the loss of salient brain functions in diseases such as multiple sclerosis (MS). The progressive and chronic nature of myelin loss in MS is not abated by current immunomodulatory therapies and thus represents a major impediment to the potential long-term success of such treatments for MS patients. Astrocytes represent a potential basis for promoting remyelination in MS. Astrocytes are the most abundant cell type in the CNS and are now recognized for their dynamic roles in neuronal and oligodendrocyte (OL) functions, including myelin homeostasis.

We have recently identified tissue inhibitor of metalloproteinases-1 (TIMP-1) as an astrocytic protein that is a trophic factor for oligodendrocytes. Clinical and experimental data support a positive correlation between elevated expression of TIMP-1 in the CNS and remyelination. For instance, in humans with acute demyelinating encephalomyelitis (ADEM), a temporary condition with complete remyelination, TIMP-1 expression is dramatically elevated. However, TIMP-1 expression is not increased in patients with MS, a chronic condition often associated with minimal remyelination. Consistent with the human condition, experimental autoimmune encephalomyelitis (EAE) in mice that over-express TIMP-1 from their astrocytes are protected from white matter injury, while mice lacking TIMP-1 (TIMP-1KO) exhibit a chronic demyelinating phenotype. We hypothesize that the loss of TIMP-1 production contributes to chronic myelin pathology in MS.

Our current and ongoing studies have developed a novel TIMP-1 conditional knockout mouse in which the timp-1 gene has been deleted from astrocytes. We have found that these mice develop a chronic demyelinating phenotype analogous to the phenotype of global knockout mice we had previously reported. Moreover, we have performed a proteomic analysis of the astrocyte secretome and identified novel and unique changes in astrocytes when  TIMP-1 is absent that correlate with human MS.