Neural Stem Cells Are Present In The Adult Brain

The ability of the central nervous system (CNS) to repair itself following injury or age-related disease is limited, and previous development of therapeutic approaches focused only on preserving at-risk neuronal populations. Yet these strategies are limited to patients where substantial neuronal loss has not already occurred. Hope for the targeting of new neurons into injured regions of the brain or expanded neural cells grafted into regions of degeneration has stemmed from the observation of endogenous generation of new neurons in the adult brain. Although once thought to be restricted to prenatal development, emerging evidence suggests that neurogenesis continues through adult life.

Researchers were surprised to learn that stem cells were present in the adult brain, an organ long thought to comprise nonrenewable neurons. The subventricular zone and the subgranular zone of the dentate gyrus of the hippocampus have the highest concentrations of dividing cells (Cameron et al., 1994). Neuronal stem cells isolated from fetal and adult brains and then cultured were induced to differentiate into the three distinct neuronal cell types—astrocytes, oligodendrocytes, and neurons (Gage et al., 2000). After transplantation, cultured stem cells engrafted into developing fetal and adult brains migrated throughout the nervous system and differentiated into tissues ranging from the hippocampus to the olfactory bulb (Gage et al., 1995; Suhonen et al., 1996). Neuronal stem cells are classified by their expression of a number of cell surface markers (CD133 positive, CD34 negative, and CD45 negative) (Uchida et al., 2000). Following expansion of adult neuronal stem cells in vitro, transplantation, and engraftment into rat brains, neural function was apparent based upon the presence of synaptic electrical activity (Auerbach et al., 2000).

Neural stem cells are defined by their ability to differentiate into the three major cell types of the CNS—neurons, astrocytes, and oligodendrocytes— in vitro. The mechanism by which this occurs in vivo has yet to be elucidated. Regulation of transcription, via Re1 silencing transcription factor mediated recruitment of histone deacetylases, is critical in the transition from neural stem cell to mature neuron (Ballas et al., 2005). Cooperation between the Smad and STAT signaling pathways is involved in gene expression and suppression during astrocyte differentiation (Sun et al., 2001). Oligodendrocytes, the myelinating glial cell type of the CNS, differentiate from a common neural-oligodendrocyte precursor through coexpression of Olig2, a basic helix-loop-helix transcription factor, and Nkx2.2 (Zhou et al., 2001). It is through a delicate interplay of transcriptional activators and repressors that neuronal stem cell fate is decided. The therapeutic potential of neural stem cells for the aging brain makes determining these factors essential.

In vitro, neural stem cells have the potential to ubiquitously give rise to neurons. In the adult brain, neurogenesis is spatially restricted to two areas, the sub-ventricular zone and the hippocampal dentate gyrus (Cameron et al., 1994). Under normal conditions, newly generated neurons are restricted to defined pathways of migration followed by highly regulated, sequential steps to integration. Although these steps are equivalent to those undergone during early development, neurogenesis in the adult brain occurs in a less permissive environment, with new adult neurons having to integrate into preexisting circuits. The quest for producing an effective therapy from induced neurogenesis relies on the discovery of several factors. These include identifying the cellular cues that are responsible for a neurogenic niche becoming permissive for neurogenesis and how the proliferation of adult neural stem cells is regulated.

Neural stem cells as therapeutic agents for age-related brain repair

The prevalence of stem cells in the nervous system appears to decline with age, as is true for a number of organ systems. The aging brain also is characterized by reduced neurogenesis. Several diseases and injuries of the brain also consist of acute neuronal loss. Parkinson's disease is distinguished by progressive loss of dopaminer-gic neurons in the substantia nigra zona compacta. A leading cause of death and disability, acute ischemic stroke causes a loss of neurons, astrocytes, and oligo-dendroctyes. Decreased neurogenesis in the adult hippocampus has been genetically linked to Alzheimer's disease, a neurodegenerative disorder of the CNS. Alzheimer's has also been linked to age-related structural deterioration and cellular senescence of the neuroprotec-tive microglia.

Though understanding the basis for age-related reduction of neurogenesis would be necessary to determine the functional contributions of newly generated neurons, preliminary studies suggest a link between neuronal replacement and phenotype recovery for disease models. In a rodent model of Parkinson's disease, treatment with TGFa and a mitogen for stem cells caused an improvement of behavioral deficits and the appearance of new neurons (Fallon et al., 2000). In a study examining the combined effects of FGF-2 and EGF on a degenerative hippocampal model, the authors observed a significant number of new neurons believed to be integrated into the hippocampal circuitry (Nakatomi et al., 2002). Behavior studies showed improved behavior recovery after growth factor treatment. Implantation of neural stem cells into the midbrains of aged mice was associated with reconstitution of neural depleted areas (Ourednik et al., 2002). Not only did this study show that aged brains can support engraftment and extensive migration of neural stem cells, but also that neural stem cells migrate more readily in the aged mouse brain than in the intact young brain.

Neural stem cells may prove to be a useful pool for age-related brain injury or disease that could be recruited or expanded in culture for transplantation to repopulate regions of neuronal loss (see Figure 45.3).

Neural Stem Cell Aging

Figure 45.3 Approaches to stem cell therapy for age-related injury or disease. There are several defined therapeutic targets for using stem cells to treat age-related injury or disease. Strategies include the isolation or recruitment of stem cells (shown in this figure are models for neural and hematopoietic stem cells) as well as targeted differentiation of embryonic stem cells. Research needs include the development of techniques for the enrichment and expansion of the stem cells in vitro, control of differentiation and cell function, as well as methods to stimulate the growth of new neurons (i.e., for neurogenesis in the brain).

Figure 45.3 Approaches to stem cell therapy for age-related injury or disease. There are several defined therapeutic targets for using stem cells to treat age-related injury or disease. Strategies include the isolation or recruitment of stem cells (shown in this figure are models for neural and hematopoietic stem cells) as well as targeted differentiation of embryonic stem cells. Research needs include the development of techniques for the enrichment and expansion of the stem cells in vitro, control of differentiation and cell function, as well as methods to stimulate the growth of new neurons (i.e., for neurogenesis in the brain).

In order for a recruitment strategy to become a viable therapy, scientists must find a way to overcome age-related loss of progenitors. Recruitment strategies must also incorporate factors involved in guided migration of newly generated neuronal progenitors to areas of injury. The alternative method, expansion of neural stem cells in vitro with subsequent transplantation, is limited by the extent to which an aged brain can tolerate grafting surgeries. Another challenge is discovering the environmental cues necessary for successful survival, differentiation, and functional integration. Certainly the field of neural stem cell research has many obstacles to overcome, but with the promise of potential therapies for neurodegenerative diseases that affect many, the light at the end of the tunnel remains a driving force.

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