Insights into neurogenesis and aging: potential therapy for degenerative disease?

Abstract

Neurogenesis is the process by which new neural cells are generated from a small population of multipotent stem cells in the adult CNS. This natural generation of new cells is limited in its regenerative capabilities and also declines with age. The use of stem cells in the treatment of neurodegenerative disease may hold great potential; however, the age-related incidence of many CNS diseases coincides with reduced neurogenesis. This review concisely summarizes current knowledge related to adult neurogenesis and its alteration with aging and examines the feasibility of using stem cell and gene therapies to combat diseases of the CNS with advancing age.

Figure 1. Neurogenesis in the adult brain is maintained in a specialized microenvironment; the neurogenic niche

(A) Neurogenesis, the production of new neurons, is spatially restricted in the mature brain to two regions, including the hippocampus within the medial temporal lobe of the human brain (boxed region). (B) Within the hippocampal formation, neurogenesis is further spatially restricted to the dentate gyrus (boxed region). (C) The dentate gyrus contains a small population of cells, clustered along the subgranular zone, that extend long apical process through the granule cell layer with terminal branching. This population of neural stem cells, designated as Type I cells, cycle slowly, express markers of immature cell phenotype, and produce, through asymmetric division, progeny, called amplifying neural progenitor cells (also known as Type II cells), that rapidly proliferate and begin to differentiate. Those neuroblasts that survive and successfully complete neuronal cell lineage specification become mature neurons that functionally integrate into the granule cell layer. The process of cell proliferation and differentiation is regulated by the local environmental expression of stimulatory and/or inhibitory signals (paired green/red arrows) that can be derived from local glial cell populations or from the local vasculature. The expression of suitable signals at an appropriate concentration orchestrates the process of stem cell proliferation, survival and differentiation. Elucidating the role of these signals will be crucial for developing therapeutic engineering of an environmental niche to stimulate endogenous neurogenesis, support the differentiation of grafted stem cells, or initiate the recruitment of endogenous stem cells in the brain for repair.

Figure 2. Approaches to the therapeutic use of stem cells

(A) Exogenous stem cells may be isolated and expanded in vitro in preparation for grafting into the brain by stereotaxic injection. The exogenous stem cells could come from a variety of sources including embryonic stem cells or tissue stem cells. Tissue stem cells could be isolated from a variety of somatic tissues, from bone marrow, or from extra-embryonic tissue, such as the umbilical cord. Induced pluripotent stem cells, derived from somatic cells that have been reprogrammed to pluripotency, may be used in research studies for the benefit they offer for understanding disease pathology. Thus, by introducing diseased stem cells to healthy brain or healthy stem cells to diseased brain, induced pluripotent stem cells could be useful for discriminating the cell autonomous deficiencies of diseased neurons relative to the environmental support offered by the diseased brain. (B) Cultured stem cells could also be genetically modified ex vivo prior to stereotaxic injection into the brain. This approach could be useful for expressing cell autonomous signals within grafted stem cells that, through autocrine or paracrine interactions, would promote successful neuronal differentiation. Alternatively, the ex vivo genetic approach could be useful for modifying stem cells to express a therapeutic transgene, thus using the stem cell as delivery vectors. (C) Gene delivery could occur directly into the CNS by stereotaxic injection to encode infected cells to express signals/factors necessary to sustain a neurogenic niche for grafted stem cells. Alternatively, in vivo gene delivery could achieve the expression of appropriate transgenes for the local recruitment of endogenous stem cells. Such therapeutic niche engineering could be used for reversing age-related decline within neurogenic niches or generating a neurogenic niche in regions that otherwise did not express the necessary signals/factors. (D) If suitable signals/factors supporting neural stem cells or recruiting endogenous neural stem cells can be identified, it may prove possible to move beyond cell- or gene delivery-mediated therapies and systemically deliver drugs or small molecules to the brain instead.