Immunological control of adult neural stem cells

Abstract

Adult neurogenesis occurs only in discrete regions of adult central nervous system: the subventricular zone and the subgranular zone. These areas are populated by adult neural stem cells (aNSC) that are regulated by a number of molecules and signaling pathways, which control their cell fate choices, survival and proliferation rates. For a long time, it was believed that the immune system did not exert any control on neural proliferative niches. However, it has been observed that many pathological and inflammatory conditions significantly affect NSC niches. Even more, increasing evidence indicates that chemokines and cytokines play an important role in regulating proliferation, cell fate choices, migration and survival of NSCs under physiological conditions. Hence, the immune system is emerging is an important regulator of neurogenic niches in the adult brain, which may have clinical relevance in several brain diseases.

Fig. 1. The adult subventricular zone in rodent

This neurogenic niche has been well-characterized by electron microscopy (A). Type-A cells (migrating neuroblasts) have an elongated cell body with one or two processes, profuse lax chromatin with small nucleoli (2 to 4), a scarce dark cytoplasm, abundant free ribosomes, microtubules oriented along the long axis of the cells, and nuclei occasionally invaginated. Their cytoplasmic membrane showed cell junctions intercalated with large intercellular spaces. Type-B cells have a light cytoplasm with a few ribosomes, extensive intermediate filaments and nuclei are typically invaginated. Their cell profiles are irregular that filled intercellular spaces between neighboring cells. Type-C cells are large and semi-spherical; their nuclei contain deep invaginations, lax chromatin occasionally clumped and large reticulated nucleoli. Type-C-cell cytoplasm is more electron-lucent than Type-A cells, but more electron-dense than Type-B cells, because it contains a few ribosomes and no intermediate filaments. Schematic drawing of the adult SVZ shows the cell organization of this region (B). Ependymal cells (Type-E cells) formed an epithelial monolayer that separates the SVZ from the lateral ventricles. These cells have spherical nuclei with lax chromatin, lateral cytoplasmic processes heavily interdigitated with apical junction complexes. The cell membrane contacting the ventricle contains microvilli and cilia, and their cytoplasm is electron-lucent with many mitochondria and basal bodies in the apical pole. A: Type-A cell; B: Type-B cell; C: Type-C cell cell; E: Ependymal cell; BV: Blood vessel; Mi: Microglia cell; V: Ventricle.

Fig. 2. Schematic drawing of adult SGZ in rodent

Dentate gyrus of adult hippocampus continuously produces new neurons throughout life. Type-B cells are the primary progenitors that give rise to intermediate progenitors named Type-D cells, which give rise to granulate neurons.

Figure 3. Microglia cells in the rodent SVZ

Iba-1 immunocytochemistry to detect microglia cells by light microscopy (A-B). In their “resting” stage microglia displays multiple thin branches, which confer a ‘bushy’ morphology to these cells. By electron microscopy (C), microglia (Mi) shows a typical dark nucleus and electrodense corpus in their cytoplasm (arrow). Frequently, microglial cytoplasmic expansions (arrow heads) are in close contact with Type-B cells. B: Type-B cell; E: Ependymal cell; V: Ventricle.

Figure 4. Effects of immune cells on aNSC

Cell effectors such as microglia, lymphocytes and leucocytes can induce a wide variety of effects on aNSC upon brain injury.

Figure 5. Immunological mediators have multiple effects on aNSC

There are some crucial steps in the neurogenic processs: Proliferation, survival, migration, differentiation. Immune effectors that affect proliferation mainly target the SVZ (1). Effectors that modulate survival and migration aim both SVZ and RMS (2), whereas immunological effects on differentiation are reflected in the olfactory bulb (3).