165 Astrocyte and Oligodendrocyte Crosstalk LIF CNTF Laminin PDGF FGF-2 IL-6 IL-8 LIF Tenascin R PDGF OPC Oligodendrocyte Astrocyte Reactive astrocyte FGF-2 TNF-α IFN-γ IL-6 BMP2, BMP4 Glutamate IL-1β TNF-α GFAP IFN-γ IL-6 Glutamate Hyaluronan Tenascin C CNTF PDGF FGF-2 IL-6 Cx43 Cx32 Cx30 Cx47 Figure 2. Astrocytes release a wide variety of molecules that impact oligodendrocyte functioning. Reactive and homeostatic astrocytes can release both beneficial (green) as well as detrimental (red) molecules. Most molecules that are secreted by astrocytes have a context dependent effect as well as a differential effect on oligodendrocytes and OPCs. Astrocyte – oligodendrocyte interplay in disease Reactive gliosis and glial scar formation Reactive astrocytes are a hallmark of many CNS diseases for example in MS lesions3,25,28,125, around the injured site during spinal cord injury (SCI)44, within Rosenthal fibres in AxD126, after ischemic stroke127, and near amyloid plaques in AD128, indicating their importance in both classic white matter and grey matter disease. Reactive gliosis is a spectrum rather than an allor-nothing reaction, and the severity may differ between diseases, patients, or even within a patient. Mildly reactive astrocytes are associated with milder CNS injury or inflammation, and do not proliferate, showing only moderate changes in gene expression. Severely reactive astrocytes are characterized by upregulation of GFAP, hypertrophy and proliferation, and are present in severe injury and infection, as well as in chronic neurodegenerative disease. The most severe reaction is the glial scar, where astrocytes proliferate and intertwine to form a physical barrier that surrounds injured CNS tissue and isolates it from healthy tissue. It is associated with severe necrosis or inflammation129. In the acute stages of CNS damage, glial scarring is essential to prevent more widespread inflammation and the spread of toxic factors, protecting neurons from secondary degeneration130. An astrocyte-specific STAT3 knock-out inhibits formation of the glial scar, and leads to increased inflammation and motor dysfunction in mice after SCI2,4,119. On the other hand, in an AD mouse model, inhibition of the JAK2-STAT3 pathway leads to reduced astrocyte reactivity and increased learning abilities131. Glial scars are also involved in restoration of BBB integrity in inflammatory CNS disorders23,130. However, in the chronic stages, the glial scars inhibit OPC migration and differentiation and is thus considered to be detrimental blocking tissue repair3,4,65,123. This is observed in ischemic
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