Within the body, normal stem cells appear to be able to divide for the lifetime of the organism because they exist in a microenvironment called a niche. These niches provide tissue support (adult stem cells are often on the basement membrane, surrounded by specific cell types called stromal cells) and signaling (between niche and stem cells, hormonal, neural, and metabolic pathways) that control the action of stem cells in a dynamic that sustains the tissue. With few exceptions, stem cells always remain in the niche and may be attached by adhesion molecules.
Researchers at the Howard Hughes Medical Institute identified the types of cells that make up the niche in Drosophila by altering/marking individual stem cells. They learned that stem cells could migrate to a new spot and function as a stem cell and that regulatory signaling could be performed by cap cells because of their abundance and constant ratio with stem cells, and they also suggested that the cap cells may act as an adhesion molecule.
The niche provides an environment in which to regulate and maintain the cells in an undiffer-entiated state and to signal when new cells are needed. This strict genetic regulation ensures that stem cells do not grow out of control. Stem cell niches have been identified in blood, brain, breast, prostate, large and small intestines, and skin. Loss of this control results from mutations in the stem cells caused by exposure to chemicals or radiation or by improper copying before cell division.
SIGNALING PATHWAYS
Signals to regulate cell behaviors include genes, and the cascade of events triggered by gene activity dictate stem cell fate and function. Among these signaling pathways are the BMI-1, Notch, Sonic Hedgehog, and Wnt genes. The Wnt signaling pathway may directly promote stem cell self-renewal, as has been shown in mice, and may influence stem cell function indirectly through the niche.
The BMI-1 (from the Polycomb group of transcription repressors) signaling pathway has been identified in hematopoietic and neuronal stem cells and is likely to regulate the self-renewal of other types of somatic stem cells. Sonic hedgehog signaling controls many aspects of growth, and studies have shown that it controls stem cell-like cells in mouse embryonic neocortex and cell proliferation in the adult ventral forebrain and in the hippocampus and that it is required for cell proliferation in the mouse forebrain’s stem cell niche.
The Notch pathway plays an important role in many stem cell niches, including the hematopoi-etic system, gut, mammary gland, and muscles. On activation, the ligand interacts with the Notch receptor in the neighboring cell and activates it to induce and maintain stem cell division.
STEM CELL DIFFERENTIATION
Adult stem cells replenish the cells lost by normal tissue turnover. When signaled to divide, the division may be asymmetric (of the two daughter cells, one remains in the niche as a stem cell and the other becomes a progenitor cell and leaves the niche to develop into a specialized cell) or symmetric (both daughter cells are stem cells that remain in the niche). The niche must provide signals telling the cells to remain undifferentiated, or they will quickly begin proliferating and differentiating, as that is the default programmed behavior and only the niche signal holds it in check. Progenitor cells move away from the niche under escort by guardian cells. Stem cells remain undifferentiated because of their unique capacity for self-renewal; with increasing specialization, they lose their pro-liferative ability and stop dividing.
In Drosophila, the placement of the mitotic spindle (perpendicular or parallel) to the cell interface results in asymmetric or symmetric division. Pluripotent mouse embryonic stem cells multiply symmetrically in culture and are suspected to be asymmetrical in the body.
If cell differentiation happened more frequently than self-renewal, the stem cell population within a niche would decrease, and if self-renewal continued unchecked, the result would be tumor development. The niche provides the necessary balance. The niche environment is responsible for the induction or inhibition of stem cell differentiation, based on the size of the niche and the composition. Signals emanating from the surrounding tissue and the supporting extracellular matrix sustain the cell identity and direct its behavior.
All functional cells arising from stem cells develop into an intermediate-differentiated progenitor cell that, through further division and differentiation through several stages, becomes a mature cell that has lost the ability to proliferate or alter its own destiny and is considered terminally generated.
In all the body systems with stem cell niches, the regenerative cells may not divide with high frequency, but the capacity for proliferation is high. By using fluorescent labeling to mark skin stem cells, researchers have shown that in response to stimulation, cells can divide rapidly within the stem cell niche.
Stem cells have the potential for regenerative medicine in repairing injured or diseased tissue and because of their purported role in tumor initiation. The niche may also play a role in cancer stem cells, making it a possible target for clinical therapy to destroy cancer as an adjunct to using chemotherapy or irradiation to destroy the proliferating tumor cells. Stem cells in the mammary gland are under the control of reproductive hormones as well as the niche to produce new tissues to create a more complex mechanism of stem cell renewal and differentiation, as well as the possibility for tumor development. A similar case is seen in the prostate, where the stem cell niche is in the basal cell layer within the region of the gland that is proximal to the urethra, which has been identified as the prostate stem cell niche.
