Discuss the role of the stem cell microenvironment in neurogenesis with reference to microglia

Neurogenesis is the generation of neurons from neural progenitor/stem cells. Until the 1960s it was believed that the nervous system was incapable of regeneration (Cajal, 1928) and that neurogenesis was limited to pre-natal development. Evidence that neurogenesis is, in fact, a life-long process was provided in 1965 by Joseph Altman’s discovery of proliferating cells in two areas of the adult rodent brain and further work, approximately 20 years later, by Fernando Nottebohm and Steve Goldman (1983). They showed new, functionally integrated neurons in adult song birds. It was determined that neurogenesis is specific to two regions within the adult mammalian central nervous system: the sub ventricular zone of the lateral ventricle and the sub granular zone of the hippocampal dentate gyrus (Alvarez-Buylla & Lim, 2004). Such work led to interest in adult human neurogenesis and Erickson et al. (1998) identified progenitor cells, demonstrating that neurogenesis in the dentate gyrus of the human hippocampus persists throughout life. This laid the foundation for the study of regulation of human neurogenesis, an area that has since been investigated in depth.

Stem cells are pluripotent cells that have the ability to regenerate. Neural stem cells are present in both the developing and the adult mammalian nervous system and they have tight control over proliferative divisions. They are therefore able to regulate the generation of a suitable number of neural progeny to populate the nervous system whilst preventing neoplastic overgrowth due to over production of self-renewing daughter cells (Morrison & Kimble, 2006). Reynold and Weiss (1992) were the first to isolate neural progenitor/stem cells from striatal tissue, providing an understanding of the origins of newly synthesised neurons in the adult CNS. The adult human brain comprises these self-renewing cells capable of generating neurons, astrocytes and oligodendrocytes (Johansson et al., 1999). These cells also generate progenitor cells which are able to self-replicate but have a more limited life span.

Neurogenesis is regulated by a spectrum of factors. The stem cell microenvironment (niche) and the signals it provides regulate maintenance, proliferation and fate commitment of the local stem cell population (Alvarez-Buylla & Lim, 2004). Microglia represent approximately 15 per cent of the total adult brain cell population (Ladeby et al., 2005). These innate immune cells are present in high density in the hippocampus and are ideally situated to influence hippocampal neurogenesis through cell-cell contact and secreted factors (Lawson & Perry, 1990). However, these secreted factors remain largely undetermined.

Microglia are morphologically subdivided into two distinct populations:

1. amboeid microglia that are widespread during embryonic and neonatal development and are considered to be precursors of 2. ramified microglia that are representative of a normal adult brain (Perry et al., 1985; Imamato & Leblond, 1978). However, this topic is the subject of much debate (Wang et al., 2002). Studies have shown pathological insults change the ramified phenotype to an activated form characteristic of withdrawn processes, enlarged cell bodies and motility. It is in this activated state that they upregulate and release immune-related markers and cytokines, causing an inflammatory response.

The detrimental effects of activated microglia have been well documented. During an inflammatory response, microglia release toxic pro-inflammatory molecules and reactive oxygen species (Kreutzberg, 1996; Streit, 2000) which, in excess, result in mature neuronal death (Boje & Arora, 1992; Chao et al., 1995; McGuire et al., 2001). Furthermore, in vivo studies have demonstrated that LPS (bacterial endotoxin) induced microglial activation, via intrathecal or systemic injection, leads to reduced neurogenesis (Ekkhdahl et al., 2003). More recently, however, studies have provided evidence for the beneficial effects of microglia for facilitation of neurogenesis.

Rats in an enriched environment activate microglia that assist in increasing neurogenesis. These activated microglia exhibit the neuroprotective factor IGF-I which is important in neural precursor proliferation in the post-natal dentate gyrus (Bartlett & Li, 1999). Activated microglia can also induce neurogenesis from SVZ neurospheres and direct neural stem cell migration. This data substantiates the evidence for the neuroprotective role of microglia (Ziv et al., 2006).

Activated microglia also release immune-related markers and cytokines following pathological or traumatic insults. Experimental models have shown a rapid induction of the cytokine IL-1beta in microglia (following actuate seizures or in kindling) in regions of the forebrain associated with epileptic activity (Eriksson et al., 1999; Vezzani et al., 1999; De Simoni et al., 2000; Ravizza & Vezzani, 2006). This is supported by clinical data that shows over expression of IL-1beta and IL-1 receptor type I in lesional brain tissue of patients with epilepsy-associated malformations (Ravizza et al., 2006a). IL-1beta has been implicated in neuronal cell loss in rodents (Allan et al., 2005) and Ravizza and colleagues (2007) have shown a link between activation of the IL-1beta system during epileptogenesis and neurodegeneration.

Neurogenesis is a complex process regulated by a spectrum of factors. The stem-cell niche plays a pivotal role in neurogenesis, as observed by studying the dynamic relationship between microglia and neurons. In their capacity as primary immune cells of the brain, microglia are able to release a diverse range of pro- and anti-inflammatory mediators (Minghetti & Levi, 1998). The role of these cytokines in neurogenesis has yet to be fully elucidated. There is much interest in cytokine IL-1beta due to its role in cognitive processes and neurological disorders such as epilepsy (Ravizza et al., 2008). Microglia are integral to the regulation of neurogenesis due to the role they play in the stem cell niche.