The Biology of Neuronal Stem Cells

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The Biology of Neuronal Stem Cells

Abstract

It has long been believed that the adult mammalian central nervous system (CNS) does not regenerate after injury (Ramón y. C., 1928). However, recent progress in stem cell biology has provided the hope that regeneration of the injured CNS might be achieved. Neural stem cells (NSC) have to the ability to re-generate and are able give rise to neurons and macroglia such as astrocytes and oligodendrocytes. This multi-functional stem cell gives great potential for neural repair in CNS disorders or injuries. With the help of new methodologies, much progress has been made in the development and characterization of neural stem cells in the adult brain. During the development of the nervous system, neural stem cells can either stay in the cell cycle and remain undifferentiated or exit the cell cycle and differentiate into its programmed specificity. Demonstration of the fate of these neural stem cells and their inducing factors would thus greatly contribute to the strategies and specific cell therapy required.

This review focuses on the nature and functional properties of neural stem cells of the mammalian central nervous system (CNS) and how they may contribute to neural repair and therapy. The subventricular zone of the forebrain (SVZ) is the most active neurogenetic area and the richest source of NSCs. These NSCs ensure a renewable source of neurons to the olfactory bulb and, when placed in culture, can be grown and extensively expanded for months, allowing the generation of stem cell lines, which maintain stable and constant functional properties. Future research of the complex mechanisms and functions of neurogenesis will provide further potential into the highly renewable and regenerative capacity of the mature central nervous system.

Acknowledgements

I would like to acknowledge and extend my heartfelt gratitude to the following persons and institutions who have made the completion of this dissertation possible:

My dissertation supervisor Dr Desmond J. Tobin, for his valuable feedback and guidance.

The University of Bradford, UK and Management Development Institute of Singapore (MDIS), for their support and assistance.

1. Introduction

Neural stem cells are multi-potent, self-regenerative cells that are able to give rise to neurons and glia cells such as astrocytes and oligodendrocytes. In addition to the central nervous system (CNS) (brain and spinal cord) neural stem cells, another population of stem cells forms neural crest-derived cells including neurons, glia, smooth muscle cells and pigmented epithelium. Neurons are the core components of the nervous system where they process and transmit information by electrochemical signalling. Glial cells provide the support and protection for neurons. The functional properties of these stem cells show its vital importance in contributing to therapy for neural repair after injury or disease.

Scientists have demonstrated that cells could be isolated from the CNS of adult and embryonic mice which proliferated in the presence of epidermal growth factor giving rise to large spheres of cells that is termed neurospheres (Reynolds and Weiss, 1992). These neurospheres possessed neurons and glia, but largely consisted of cells expressing the intermediate filament previously associated with neuroepithelial cells, nestin. They showed that a single cell could be propagated into an entire neurosphere that could subsequently produce a new neurosphere containing neurons and glia, thus presenting the self-renewing, multi-potent properties of stem cells.

Neural stem cells in the adult brain have been shown to have important differences from those in the developing brain. One of the most important characteristics of neural stem cells is their choice of cell fate which contributes to the specification of neuro-subtype for therapy. Many potential therapeutic applications will call for the regeneration or replacement of specific cell types, glutamatergic neurons for stroke, dopaminergic neurons for Parkinson disease, and oligodendrocytes for spinal cord injury or demyelinating disease.

Fig 1. During development, early neuro-ectodermal stem cells generate two subpopulations of multipotent neural stem cells: Central nervous system-derived neural stem cells (CNS-NSC) that give rise to neurons and glia of the CNS and neural crest stem cells that generate the neurons and glia of the peripheral nervous system (PNS), including the enteric nervous system (ENS), as well as other non-neural lineages.

2. Neural Crest and Neurogenesis

The neural crest, a transient component of the ectoderm, is located in between the neural tube and the epidermis of an embryo during neural tube formation. Neural crest cells quickly migrate during or shortly after neurulation, which is an embryological event marked by neural tube closure.

It has been referred to as the fourth germ layer, due to its great importance. The neural crest can give rise to neurons and glia of the autonomic nervous system (ANS), skeletal elements, tendons and smooth muscle; chondrocytes, osteocytes, melanocytes, chromaffin cells, and supporting cells and hormone producing cells in certain organs.

Fig 2. Neurogenesis in the adult mammalian brain. Neurogenesis occurs primarily in the subgranular zone (SGZ) of the dentate gyrus (DG) and the subventricular zone (SVZ). Newly generated neuronal cells in the SGZ migrate to the granule layer, where they extend axonal projections to the CA3 area. Newly generated neuronal cells in the SVZ migrate to the olfactory bulb (OB), through the rostro-migratory stream (RMS), where they differentiate into inter-neurons of the OB.

The generation of neural cells such as neurons and glial cells of the nervous system is termed neurogenesis (Fig. 2). This process occurs in the adult brain from neural stem cells (NSCs) that reside in the adult central nervous system (CNS). Neurogenesis occurs primarily in 2 areas of the adult brain in the mammals; the dentate gyrus (DG) of the hippocampus, and the sub-ventricular zone (SVZ). (Eriksson et al, 1998; Curtis et al, 2007) In the DG, newly generated neuronal cells in the subgranular zone (SGZ) migrate to the granule cell layer, where they project to the CA3 area of Ammon's horn. Newly generated neuronal cells in the SVZ migrate to the olfactory bulb (OB), through the rostro-migratory stream (RMS), where they differentiate into interneurons of the OB.

In the adult human brain, (Eriksson et al, 1998) reported the presence of dividing cells in the DG, co-labelled with neuronal markers, from tissue samples obtained postmortem, providing the first evidence that neurogenesis occurs in the adult human brain. (Sanai et al, 2004) reported the existence of a ribbon of astrocytes lining the lateral ventricles of adult human brain tissue samples that proliferate in vivo and behave as clonal precursor cells of self-renewing, multipotent neurospheres in vitro, suggesting that a substantial number of neural stem cells (NSCs) exist in the adult human brain throughout life and identifying SVZ astrocytes as NSCs in the adult human brain. (Sanai et al, 2004) however reported no further evidence of chains of migrating neuroblasts in the SVZ or in the pathway to the OB. These results may possibly mean that the migration of newly generated neuronal cells from the SVZ to the OB does not take place in adult humans.

3. Neural Stem Cells in the Adult and Developing Brain

It has been studied that newly generated neuronal cells originate from NSCs in the adult brain. NSCs are the self renewing, multipotent cells that generate the neuronal and glial cells of the nervous system. (Gage, 2000) To identify the existence of NSCs in the adult brain, investigators have aimed at isolating and characterising in vitro, cells with self-renewing and multipotent properties. The demonstration that NSCs are multipotent relies on showing that the 3 main phenotypes of the CNS, neurons, astrocytes and oligodendrocytes, can be expressed and generated from single cells. (Taupin and Gage, 2002)

The demonstration that these NSCs can self-renew relies on showing that cells maintain their multi-potentiality over time. (Taupin and Gage, 2002) However, these criteria although well accepted, are not enough to demonstrate the existence of NSCs. The main arguements are in the number of sub-cloning steps that the experiment must present to qualify that it is a self-renewing cell. Since stem cells have the ability to give rise to a large number of progeny, it is proposed to at least demonstrate self-renewal over an extended period of more than 5 passages. These must then be together with the generation of a large number of progeny, amplified to numbers more numerous than the initial population. (Reynolds and Rietze, 2005) Undifferentiated cells with limited proliferative capacity that cannot self-renew are qualified as neural progenitor cells (NPCs).

3.1 The Adult Brain

In 1992, (Reynolds and Weiss) reported the first isolation and characterisation in vitro of NPCs from the adult brain. The investigators isolated, from the adult striatal area containing the SVZ of adult mice, a population of undifferentiated cells expressing nestin, that differentiate into the main phenotypes of the nervous system, neuronal, astrocytic and oligodendrocytic cells. Isolated cells grew as neurospheres, in defined medium in the presence of epidermal growth factor (EGF). Nestin is an intermediate filament that has been characterised as a marker for neuroepithelial and CNS stem cell during development (Reynolds and Weiss, 1992), and thus with this finding may suggest that it can be considered as a marker for adult neural progenitor and stem cells (Frederiksen K, McKay, 1988). Although mostly expressed in nerve cells, nestin is also expressed in follicle stem cells and their immediate, differentiated progeny. The hair follicle bulge area is an abundant, easily accessible source of actively growing pluripotent adult stem cells which can potentially differentiate into neurons, glia, keratinocytes, smooth muscle cells and melanocytes in vitro. (Hoffman, 2007) This indicates that hair follicle stem cells may provide an effective, accessible, alternative source of stem cells for treatment of peripheral nerve injury.

In 1995, (Gage et al, 1995) isolated and characterised in vitro a population of cells with similar properties from the adult rat hippocampus. The isolated cells were grown as monolayers in the presence of basic fibroblast growth factor (FGF-2) in a defined medium. Further in vitro studies were done that demonstrated these populations of cells as self-renewing, multi-potent NSCs. (Gritti et al, 1996; Palmer et al, 1997).

Since then, self-renewing, multipotent neural progenitor and stem cells have been isolated and characterised from various areas of the adult CNS, including from non-neurogenic areas, like the spinal cord, from various species, including humans. (Taupin and Gage, 2002) These studies suggest that self-renewing multipotent NSCs reside in the adult CNS, particularly in the SVZ and the hippocampus.

Work by (Doetsch et al, 1999) gave strong evidence that a glial fibrillary acidic protein (GFAP)-expressing cell in the subventricular (subependymal zone) is capable of replenishing the SVZ after depletion and give rise to neurons in vitro and in vitro. In the same year, (Laywell et al, 1999) demonstrated that, in vitro, GFAP containing cells grown as traditional “astrocyte” cultures can form neurospheres and lead to the formation of neurons as well as glia. These results possibly imply that the adult forebrain stem cells are located in the SVZ and may mostly be GFAP positive. Further studies demonstrated that the vast majority of neurosphere-forming cells derived from the murine forebrain are GFAP positive (Imura et al, 2003; Imura et al, 2006). Investigators also indicated that majority, of not all postnatally produced neurons are primarily originated from GFAP positive cells (Garcia et al, 2004).

Transgenically targeted cell fate mapping showed that essentially all new neuronal cells generated in the adult mouse forebrain in vivo, and in adult multipotent neurospheres in vitro, derived from progenitor cells that expressed GFAP (Morshead et al, 2003). Constitutively dividing GFAP expressing progenitors showed predominantly bipolar or unipolar morphologies with significantly fewer processes than non-neurogenic multipolar astrocytes (Garcia et al, 2004). These findings highlight the morphologically distinctive GFAP-positive progenitor cells as the predominant source of constitutive adult neurogenesis, further supporting a glial origin for newly generated neuronal cells in the adult brain (Taupin, 2006).

3.2 The Developing Brain

Neural stem cells in the developing brain appear to bear important differences from those in the adult brain. Before embryonic day 15 in the mouse, there are no significant amount of GFAP positive cells within the brain (Fox et al, 2004). Because cells that meet at least some of the criteria of neural stem cells (self-renewing and multipotent) (Gage, 2000) can be cultured from any embryonic stage after neural tube formation, and possibly before, these cells must be different to some extent from adult neural stem cells. However, there is no evidence of a quiescent, slowly dividing neural stem cell during early brain development.

A study showed that neural stem cell colonies derived from cortex and spinal cord of embryonic day (E) 14.5 mice differentially expressed regional marker genes along the anteroposterior axis (Zappone et al., 2000). This suggests that neural stem cells may possess intrinsic regional identity, which, for example, can be maintained in the absence of their in vivo environment. It makes sense because a great deal of stem cell proliferation would be required to generate the large numbers of cells in the mammalian brain. Furthermore, it is apparent that neural stem cells change their characteristics during development. (Kornblum, 2007) In vivo, a wave of neurogenesis occurs before gliogenesis. Using clonal cell culture combined with long-term time-lapse video microscopy, researchers (Qian et al, 2000) show that isolated stem cells from the embryonic mouse cerebral cortex exhibit a distinct order of cell-type production: neuroblasts first and glioblasts later.

Neural stem cells cultured from early to mid-gestation give rise to more neurons than those cultured at later periods, a property that appears to be cell-intrinsic, where they are capable to manipulate the generation neurons versus glia in response the mitogen epidermal growth factor (EGF) (Qian et al, 2000). These properties, however, are subject to manipulation. Deletion of the tumor suppressor gene, PTEN, for example, allows neural stem cells derived from embryonic mouse cortex to retain their neurogenic capacity for longer periods in culture (Groszer et al, 2001; Groszer et al, 2006). As in the adult, the cellular source for neural stem cells in the developing brain is being intensively studied. As mentioned earlier, nestin is an intermediate filament expressed by the neuroepithelial cells of the neural tube (Lendahl et al, 1990). Nestin-positive cells make contact with the ventricular surface and have radially oriented processes that make contact with the pial surface. (Kornblum, 2007) These cells become radial glia, which have long been known to play key roles in radial migration of nascent neurons. However, many studies have now clearly demonstrated that radial glia of the developing brain function as neural stem cells, giving rise to neurons, glia and other neural stem cells (Anthony et al, 2004; Malatesta et al, 2003).

4. Choice of Neural Cell Fate

Embryonic neural stem cells can either proliferate; thereby maintaining a pool of undifferentiated neural progenitor cells, or differentiate into neurons or macroglial cells like astrocytes and oligodendrocytes. Astrocytes anchor neurons to their blood supply while oligodendrocytes are cells that coat axons in a neuron. In the developing nervous system two principal factors determine the fate of the differentiating neurons or glia: the position of the neural progenitor cell within the neuroepithelium and the timing of initiation of its differentiation (Valérie et al, 2008).

In the developing spinal cord, the ventricular zone contains neural progenitor cells that are subdivided into groups destined for distinct neuronal differentiation (Briscoe et al). At early developmental stages, the ventral neural progenitor cells, termed progenitors of motor neurons (pMNs), can produce motor neurons, while at later stages they differentiate into oligodendrocytes. Motor neurons receive signals from the brain and spinal cord to and cause muscle contractions and affect glands. Oligodendrocytes on the other hand, wraps around the axon of a neuron in the CNS forming the myelin sheath to provide insulation to the axon (Baumann et al, 2001). The pMNs express homeodomain transcription factors, leading to the activation of the basic helix-loop-helix (bHLH) transcription factor Olig2 (Briscoe et al, 2000; Mizuguchi et al, 2001; Novitch et al, 2001; Zhou et al, 2001; Lee et al, 2005).

4.1 Transcription Factors Influencing Cell Fate

It has been suggested that a collection of transcription factors, predominately homeodomain proteins such as Pax7, Pax6, Nkx6.1 and the above mentioned Oligo2 are important intermediates in the process of how positional identity imposed on neural progenitor cells determines neuronal subtype specification (Ericson et al, 1997a, 1997b; Briscoe et al, 1999, 2000; Sander et al, 2000; Novitch et al, 2001; Vallstedt et al, 2001). For example, the forced expression of Neurogenin 1 in cultured embryonic telencephalic stem cells induces neuronal differentiation (Sun et al, 2001). On the other hand, over-expression of a constitutively activated Notch receptor results in a glial cell fate (Morrison et al, 2000; Irvin et al, 2003). These transcription factors are mostly regulated by sonic hedgehog (SHH) signalling, an important signalling pathway during embryonic development. Expression of these proteins are repressed or expressed according to the threshold of graded SHH signalling (Ericson et al, 1997a, 1997b; Briscoe et al, 1999, 2000; Sander et al, 2000; Novitch et al, 2001; Vallstedt et al, 2001). From these results we can infer that the profile expression of these homeodomain proteins appears relate to a transcriptional code that determines the positional identity of the progenitors and its subsequently fated neural subtype.

Olig2 is highlighted as a key nodal point in the process of cell-fate choice, contributing to the regulation of both homeodomain transcription factors, which determine motor neuron subtype identity, and bHLH factors, like the proneural factor neurogenin 2 (Ngn2), which drives neurogenesis. Oligodendrocyte production requires the ongoing activity of Olig2 and is preceded by downregulation of Ngn2, a determinant of the neuron-glial switch (Rowitch, 2004). While oligodendrocytes retain the capacity to divide after leaving the neural progenitor domain, neuronal progenitor cells exit the cell cycle prior to initiating migration and differentiation in the mantle layer of the neural tube during development. This may possibly mean that cell exit is required for differentiation. However researchers have demonstrated that cell cycle exit alone is insufficient to trigger neuronal differentiation (Garcia et al, 2003; Hardcastle and Papalopulu, 2000).

4.2 Cell Cycle Regulation Influencing Cell Fate

To establish more clearly the importance of the temporal regulation of cell cycle exit on cell-fate choice, (Valérie et al, 2008) tested the effect of forced cycling on the specification and timing of differentiation. To this end, they tested the fate of pMNs, which temporally resulted in two distinct cell types, motor neurons and oligodendrocytes, following the forced expression of CyclinD; that keeps neural progenitor cells proliferating, preventing neuronal differentiation. Their results showed that forcing pMNs to cycle does not alter the production of motor neurons but, rather, results in transgenic cells migrating to the differentiating field and differentiating whilst cycling (Valérie et al, 2008). These findings demonstrate that forcing the cells to remain in the cell cycle is not sufficient to maintain a reservoir of undifferentiated neural progenitor cells; instead the cycling cells proceeded into the right pathway with their programmed specification and differentiation, regardless of cell cycle exit or progression.

5. Neural Stem Cells in Therapy

The evidence that neurogenesis occurs in the adult brain and that NSCs are present in the adult CNS indicates that diseases in the adult CNS may be susceptible to repair, and opens new opportunities for cellular therapy. Cells lost during disease can be replaced by stimulation of endogenous stem cells already present in the brain, or by transplantation of new adult-derived stem cells into the damaged region as an exogenous source. Neural progenitor and stem cells have been isolated and characterised in vitro from various areas, neurogenic and non-neurogenic - including the spinal cord - of the adult brain, suggesting that neural progenitor and stem cells reside throughout the adult CNS (Reynolds and Weiss, 1992; Gage et al, 1995).

Hence, hypothetically, regeneration and repair of the diseased or injured nervous system could be induced by locally stimulating neural progenitor and stem cells at the sites of degeneration. Other evidences show that new neuronal cells are generated at sites of degeneration in the diseased brain and after CNS injuries, where they replace some of the degenerated nerve cells (Arvidsson et al, 2002; Curtis et al, 2003). The SVZ origin of these newly generated neuronal cells suggests that conditions enhancing SVZ neurogenesis could promote regeneration and functional recovery after CNS injuries (Komitova et al, 2005).

Neural progenitor and stem cells can be isolated from the adult brain providing a valuable source of tissue for cellular therapy. Adult-derived NSCs elicit several advantages over other cell types for cellular therapy, among them, the ability to perform autologous transplantation, in which neural progenitor and stem cells would be isolated from an undamaged area of the CNS, grown in culture, and grafted back to restore brain function.

The ability to perform autologous transplantation indicates a significant advantage for adult-derived neural progenitor and stem cells over other cell types for cell transplantation method. This would not only eliminate the need to find a matching donor, it would also conveniently forego the use of immune-suppressive drugs, like cyclosporine which only makes the patient weaker. On the other hand, obtaining neural progenitor and stem cells from patients would involve invasive surgery, risks of adverse immunological response and more importantly, the destruction of healthy tissues, limiting its clinical effectiveness. Neural progenitor and stem cells have also been isolated from human post-mortem tissues (Palmer et al, 2001; Schwartz et al, 2003), providing an alternative source of tissues for cellular therapy. Hair follicle stem cells in the skin are also found to have the ability of differentiating into neurons, glial cells, keratinocytes and smooth muscle cells in vitro. Implanted into the gap region of a severed sciatic nerve in mice, the hair follicle stem cells greatly enhanced the rate of nerve regeneration and the restoration of nerve function (Hoffman, 2006). These results suggest that hair-follicle stem cells provide yet another alternative to an important accessible, autologous source of adult stem cells for regenerative medicine.

6. Conclusion

The field of neural stem cells is in a state of rapid growth. With the significant evidence that neurogenesis occurs in the adult brain and that NSCs can be found in the adult CNS, determining the identification, source, and functions of newly generated neuronal cells has been the subject of extensive research, debates and controversies. Nevertheless, neural stem cells emphasises one of the most amazing discoveries of the last decade. It is of great interest that cells isolated from what has long been viewed as the most quiescent among the bodily tissues can display such an astonishing extent of plasticity and, equally important, such an amazing self-renewing and multi-potent ability.

Most importantly, the availability of a renewable and multi functional source of human neural cells promises to open new doors in clinical medicine and unpredictable therapeutic strategies for the treatment of injuries and disorders associated with the central nervous system.

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