Stem cells in the nervous system

Abstract

Given their capacity to regenerate cells lost through injury or disease, stem cells offer new vistas into possible treatments for degenerative diseases and their underlying causes. As such, stem cell biology is emerging as a driving force behind many studies in regenerative medicine. This review focuses on the current understanding of the applications of stem cells in treating ailments of the human brain, with an emphasis on neurodegenerative diseases. Two types of neural stem cells are discussed: endogenous neural stem cells residing within the adult brain and pluripotent stem cells capable of forming neural cells in culture. Endogenous neural stem cells give rise to neurons throughout life, but they are restricted to specialized regions in the brain. Elucidating the molecular mechanisms regulating these cells is key in determining their therapeutic potential as well as finding mechanisms to activate dormant stem cells outside these specialized microdomains. In parallel, patient-derived stem cells can be used to generate neural cells in culture, providing new tools for disease modeling, drug testing, and cell-based therapies. Turning these technologies into viable treatments will require the integration of basic science with clinical skills in rehabilitation.

Figure 1. Stem cells self-renew and give rise to differentiated progeny

A. Stem cells (black) divide to form another stem cell (self-renewal) and a progenitor cell (light grey). Progenitor cells divide to amplify their number, and in turn give rise to more differentiated progeny (white). B. Stem cells reside in specialized niches, which provide important positional cues and regulatory elements that influence stem cell behavior. When a stem cell divides, the daughter cell that retains a stem cell identity is kept within the boundaries of the niche, while the other daughter cell loses the constraint on its phenotype. This second daughter cell now forms undifferentiated progenitors, which in turn give rise to more differentiated progeny.

Figure 2. Endogenous adult neural stem cells and their niche

A. Schema of a sagittal section of an adult mouse brain showing the V-SVZ adjacent to the lateral ventricles and SGZ of the hippocampal formation. New neurons born in the V-SVZ migrate a long distance to their final destination in the olfactory bulb (arrow). In contrast, adult-born neurons in the SGZ integrate locally into the circuitry. B Schema of cell types and the anatomy of adult neurogenic niches. The V-SVZ niche (left) is composed of astrocyte NSCs (black) which contact the ventricular lumen between multiciliated ependymal cells, and which extend a radial process that contacts blood vessels. These cells give rise to amplifying progenitors (light grey), which in turn differentiate to migrating immature neurons (white). These immature neurons migrate to the olfactory bulbs, where they mature into interneurons. NSCs and progenitors often directly contact blood vessels at specialized sites that lack astrocyte end feet. The SGZ niche (right) is also composed of astrocyte NSCs (black) in contact with blood vessels, but these cells do not contact the ventricular lumen. SGZ NSCs also give rise to immature neurons through progenitors, and these neurons travel along the radial processes of the NSCs to integrate within the local circuitry. Local interneurons regulate SGZ NSCs. C Schema showing adult neural stem cell niches in the human brain. Future mechanistic studies on the biology of both regions will provide important insight into how to harness these endogenous NSCs and exploit their therapeutic potential. By modulating molecular pathways that regulate adult NSCs, it may eventually be possible to stimulate astrocytes elsewhere in the brain to become NSCs.

Figure 3. Making motor neurons from stem cells

Embryonic stem cell lines (ESCs) are generated from early human embryos, whereas differentiated skin cells can be turned into induced pluripotent stem cells (iPSCs) by upregulating specific stem cell genes. Both ESCs and iPSCs can be directed to differentiate into motor neurons through a multi-step process by culturing them for weeks in the presence of factors that mimic normal neuronal development (“directed differentiation”). A more rapid process (days) is the “direct reprogramming” of ESCs (or fibroblasts, not shown) into motor neurons directly by forced expression of motor neuron genes.

Figure 4. Human ALS in the culture dish

To date, human ALS astrocytes have been shown to be toxic for mouse ESC-derived motor neurons, as are mouse ALS astrocytes for human ESC-derived motor neurons. The ideal system would be a completely humanized model as depicted here, in which astrocytes (light grey) are derived from post mortem brain or ALS ESCs/iPSCs and motor neurons (dark grey) are generated from ESCs/iPSCs. If human astrocytes lead to spontaneous motor neuron degeneration in this simplified culture system it should be possible to test drugs for their efficacy in preventing ALS-related motor neuron cell death, as well as study the cellular and molecular mechanisms underpinning disease progression.

Figure 5. Tapping the potential of stem cells for human health

A parallel focus on the two main areas of research outlined in this review – endogenous stem cells and their niche, and disease modeling – provides a basis for three novel areas of progress toward clinical application and regenerative medicine.