Gliogenesis

Introduction

Brain pathophysiology is influenced by a dynamic balance between deleterious and beneficial responses to the initial insult . Stroke and brain injury trigger a wide spectrum of neurovascular perturbations, glial activation, and secondary neuroinflammation that may all amplify neuronal cell death cascades. But at the same time, many endogenous neuroprotective responses may also be activated (review by Moskowitz et al. ), and these beneficial processes include compensatory gliogenesis.

Gligogenesis (e.g., generation of astrocytes and oligodendrocytes) occurs both in developing and adult brain. During embryogenesis and development, multipotential progenitor cells generate new neurons, astrocytes, and oligodendrocyte lineage cells in germinal zones. In the adult brain, the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) in the dentate gyrus of hippocampus retain multiple stem cells to form the largest germinative areas for new neurons and glial cells. Although the rate of neurogenesis and gliogenesis is much lower in adult brain than in developing brain, adult neurogenesis and gliogenesis may increase after brain injury to repair damaged brain tissue.

Historically, neurons and glial cells (e.g., astrocytes and oligodendrocytes) have been thought to derive from distinct precursor pools, partly because glial cells appear after neurons emerge during development. However, studies have proposed that some populations of glial cells may work as a neural stem cell and give rise to differentiated neurons (and differentiated glial cells, as well). This chapter will first introduce basic processes for neurogenesis and gliogenesis during development. And then, mechanisms of adult gliogenesis under physiological and pathological conditions will be discussed.

Radial Glia Gives Rise to Neurons and Glial Cells During Development

The term “glial cell” has been used in different ways in the literature. For a long time, glial cells have been considered as differentiated nonneuronal cells that support nerve cells and regulate metabolic activity in the central nervous system. However, the term “glial cell” now refers to both a progenitor population that gives rise to brain cells (e.g., neurons, astrocytes, oligodendrocytes) as well as a differentiated population of parenchymal astrocytes and oligodendrocytes (and sometimes ependymal cells and microglia). In fact, during development, radial glial cells express astrocytic markers and make an astrocyte-like contact with endothelial cells, but at the same time, those cells play a role as neural stem cells to generate differentiated neurons and glial cells. (The term “neural stem cell” is also somewhat confusing, but this chapter follows the definition by Kriegstein and Alwarez-Buylla and uses the term “neural stem cell” to refer to the primary progenitor cells that initiate lineages leading to the formation of differentiated neurons or glial cells.)

During the early embryonic stage of brain development, neuroepithelial cells convert into radial glial cells that are morphologically characterized by the projection of its processes from the ventricular zone to the meningeal zone with apicobasal polarity. Radial glial cells contact the ventricle apically and the meninges, basal lamina, and blood vessels basally. Radial glia may have three major roles: self-proliferation, neurogenesis, and gliogenesis. For self-proliferation, radial glial cells divide symmetrically. But for neurogenesis and gliogenesis, they divide asymmetrically.

Before gliogenesis takes place during embryonic development, radial glia generates neurons directly via asymmetric proliferation or indirectly through intermediate progenitor cells (so-called neurogenic intermediate progenitor cells; nIPCs). During the late embryonic stage, most radial glial cells begin to detach from the apical side and generate astrocytes via direct conversion or through astrocytic intermediate progenitor cells. In a parallel to astrocyte generation, radial glial cells also generate oligodendrogenic intermediate progenitor cells [oIPCs, also known as oligodendrocyte precursor cells (OPCs)], which then differentiate into oligodendrocytes at the end of embryonic development or after birth ( Fig. 18.1 ).

After birth, a subpopulation of radial glial cells that reside at the apical side continues to generate nIPCs and oIPCs for physiological neurogenesis and oligodendrogenesis. However, eventually, some of these neonatal radial glial cells convert into ependymal cells and others into the adult SVZ astrocytes (also known as type B cells) over time. In the adult brain, there are two major subtypes of glial cells that work as a neural stem cell to generate differentiated neurons and glial cells. The first subset comprises adult SVZ astrocytes (type B cells) that contact ependymal cells apically and blood vessels basally. The second subset comprises a subpopulation of astrocytes in SGZ in the dentate gyrus of hippocampus (so-called adult SGZ astrocytes), which may derive from radial glia during embryonic development.