Glial development: the crossroads of regeneration and repair in the CNS

Abstract

Given the complexities of the mammalian CNS, its regeneration is viewed as the holy grail of regenerative medicine. Extraordinary efforts have been made to understand developmental neurogenesis, with the hopes of clinically applying this knowledge. CNS regeneration also involves glia, which comprises at least 50% of the cellular constituency of the brain and is involved in all forms of injury and disease response, recovery, and regeneration. Recent developmental studies have given us unprecedented insight into the processes that regulate the generation of CNS glia. Because restorative processes often parallel those found in development, we will peer through the lens of developmental gliogenesis to gain a clearer understanding of the processes that underlie glial regeneration under pathological conditions. Specifically, this review will focus on key signaling pathways that regulate astrocyte and oligodendrocyte development and describe how these mechanisms are reutilized in these populations during regeneration and repair after CNS injury.

Figure 1. Development of the Astrocyte Lineage

Schematic synopsis of the cellular and molecular processes that oversee the specification and differentiation of the astrocyte lineage. Unlike neuronal- or oligodendrocyte- lineage development, the intermediate stages of astrocyte lineage development remain poorly defined, due in part, to the lack of reliable markers and clearly defined functionalendpoints.

Figure 2. Astrocyte Roads to Reactivity

The two key processes associated with astrocyte development that directly contribute to the reactive astrocyte phenotype are, proliferation and GFAP-induction. Molecular regulation of these processes during development is viewed as the road to astrocyte reactivity and understanding how they are recapitulated after injury will serve as a starting point for understanding the nature of reactive astrocytes.

Figure 3. Positive and negative regulators of oligodendrocyte development and regeneration

Schematic synopsis of the major developmental phases of oligodendrocyte maturation - i.e. proliferation, cell cycle exit/differentiation and myelination – after demyelination of the adult brain. Green arrows refer to enhancers of these processes under pathological conditions, whereas red arrows refer to inhibitory pathways. Preventing or suppressing the inhibitory effects of specific pathways, as well as leveraging on enhancers promotes oligodendrocyte maturation and myelination, and might define future cell-based therapeutic approaches to demyelinating diseases.

Figure 4. Oligodendrocyte regeneration through lineage plasticity of GAD-expressing neuroblasts

Demyelination of the adult white matter (corpus callosum) causes fate plasticity in GAD-expressing (GAD+) neuroblasts of the subventricular zone (SVZ). Under normal physiological conditions, Olig2 expression is repressed by BMP signaling in GAD+ neuroblasts. Demyelination causes upregulation in the levels of the BMP antagonist chordin in the SVZ, which prevents BMP signaling and results in induction of Olig2 expression in GAD+ cells. These cells migrate out of the SVZ into the corpus callosum, where they generate mature, myelinating oligodendrocytes (see Jablonska et al., 2010).