Adult stem cells are undifferentiated cells, found throughout the body after development, that multiply by cell division to replenish dying cells and regenerate damaged tissues. They are also known as somatic stem cells (from Greek σωματικóς, meaning of the body). Unlike embryonic stem cells, they can be found in juvenile and adult animals, including humans.
Scientific interest in adult stem cells is centered around two main characteristics. The first of which is their ability to divide or self-renew indefinitely, and the second their ability to generate all the cell types of the organ from which they originate, potentially regenerating the entire organ from a few cells. Unlike embryonic stem cells, the use of human adult stem cells in research and therapy is not considered to be controversial, as they are derived from adult tissue samples rather than human embryos designated for scientific research.
The main functions of adult stem cells are to replace cells that are at risk of possibly dying as a result of disease or injury and to maintain a state of homeostasis within the cell. There are three main methods to determine if the adult stem cell is capable of becoming a specialized cell. The adult stem cell can be labeled in vivo and tracked, it can be isolated and then transplanted back into the organism, and it can be isolated in vivo and manipulated with growth hormones. They have mainly been studied in humans and model organisms, such as mice, rats and planarians.
Structure Defining properties
A stem cell possesses two properties: Self-renewal is the ability to go through numerous cycles of cell division while still maintaining its undifferentiated state. Stem cells can replicate several times and can result in the formation of two stem cells, one stem cell more differentiated than the other, or two differentiated cells. Multipotency or multidifferentiative potential is the ability to generate progeny of several distinct cell types, (for example glial cells and neurons) as opposed to unipotency, which is the term for cells that are restricted to producing a single cell type. However, some researchers do not consider multipotency to be essential and believe that unipotent self-renewing stem cells can exist. These properties can be illustrated with relative ease in vitro, using methods such as clonogenic assays, where the progeny of a single cell is characterized. However, it is known that in vitro cell culture conditions can alter the behavior of cells, proving that a particular subpopulation of cells possesses stem cell properties in vivo is challenging, and so considerable debate exists as to whether some proposed stem cell populations in the adult are indeed stem cells.
Properties Cell division To ensure self-renewal, stem cells undergo two types of cell division (see Stem cell division and differentiation diagram). Symmetric division gives rise to two identical daughter stem cells, whereas asymmetric division produces one stem cell and one progenitor cell with limited self-renewal potential. Progenitors can go through several rounds of cell division before finally differentiating into a mature cell. It is believed that the molecular distinction between symmetric and asymmetric divisions lies in the differential segregation of cell membrane proteins (such as receptors) and their associated proteins between the daughter cells.
Under normal conditions, tissue stem cells divide slowly and infrequently. They exhibit signs of quiescence or reversible growth arrest. The niche the stem cell is found in plays a large role in maintaining quiescence. Perturbed niches cause the stem cell to begin actively dividing again to replace lost or damaged cells until the niche is restored. In hematopoietic stem cells, the MAPK/ERK pathway and PI3K/AKT/mTOR pathway regulate this transition. The ability to regulate the cell cycle in response to external cues helps prevent stem cell exhaustion or the gradual loss of stem cells following an altered balance between dormant and active states. Infrequent cell divisions also help reduce the risk of acquiring DNA mutations that would be passed on to daughter cells.
Plasticity Discoveries in recent years have suggested that adult stem cells might have the ability to differentiate into cell types from different germ layers. For instance, neural stem cells from the brain, which are derived from ectoderm, can differentiate into ectoderm, mesoderm, and endoderm. Stem cells from the bone marrow, which is derived from mesoderm, can differentiate into liver, lung, GI tract, and skin, which are derived from endoderm and mesoderm. This phenomenon is referred to as stem cell transdifferentiation or plasticity. It can be induced by modifying the growth medium when stem cells are cultured in vitro or by transplanting them to an organ of the body different from the one they were originally isolated from.
There is yet no consensus among biologists on the prevalence and physiological and therapeutic relevance of stem cell plasticity. More recent findings suggest that pluripotent stem cells may reside in blood and adult tissues in a dormant state. These cells are referred to as "Blastomere Like Stem Cells" (BLSCs)Am Surg. 2007 Nov; 73: 1106–1110 and "very small embryonic-like" (VSEL) stem cells, and display pluripotency in vitro.
As BLSCs and VSEL cells are present in virtually all adult tissues, including the lungs, brain, kidneys, muscles, and pancreas, co-purification of BLSCs and VSEL cells with other populations of adult stem cells may explain the apparent pluripotency of adult stem cell populations. However, recent studies have shown that both human and murine VSEL cells lack stem cell characteristics and are not pluripotent.
Aging Stem cell function becomes impaired with age, and this contributes to progressive deterioration of tissue maintenance and repair. A likely important cause of increasing stem cell dysfunction is an age-dependent accumulation of DNA damage in both stem cells and the cells that comprise the stem cell environment. (See also DNA damage theory of aging.)
Adult stem cells can, however, be artificially reverted to a state where they behave like embryonic stem cells (including the associated DNA repair mechanisms). This was done with mice as early as 2006 with prospects to slow down human aging substantially. Such cells are one of the various classes of induced stem cells.
Function Signaling pathways Adult stem cell research has been focused on uncovering the general molecular mechanisms that control their self-renewal and differentiation. Notch The Notch pathway has been known to developmental biologists for decades. Its role in the control of stem cell proliferation has now been demonstrated for several cell types including hematopoietic, neural, and mammary stem cells. Wnt These developmental pathways are also strongly implicated as stem cell regulators. TGFβ The TGFβ family of cytokines regulate the stemness of both normal and cancer stem cells.
Types
Hematopoietic stem cells
Hematopoietic stem cells (HSCs) are stem cells that can differentiate into all blood cells. This process is called hematopoiesis. Hematopoietic stem cells are found in the bone marrow and umbilical cord blood. The HSCs are generally dormant when found in adults due to their nature.
Mammary stem cells
Mammary stem cells provide the source of cells for the growth of the mammary gland during puberty and gestation and play an important role in the carcinogenesis of the breast. Mammary stem cells have been isolated from human and mouse tissue as well as from cell lines derived from the mammary gland. Single such cells can give rise to both the luminal and myoepithelial cell types of the gland and have been shown to have the ability to regenerate the entire organ in mice.
Intestinal stem cells
Intestinal stem cells divide continuously throughout life and use a complex genetic program to produce the cells lining the surface of the small and large intestines. Intestinal stem cells reside near the base of the stem cell niche, called the crypts of Lieberkuhn. Intestinal stem cells are probably the source of most cancers of the small intestine and colon.
Mesenchymal stem cells
Mesenchymal stem cells (MSCs) are of stromal origin and may differentiate into a variety of tissues. MSCs have been isolated from the placenta, adipose tissue, lung, bone marrow and blood, Wharton's jelly from the umbilical cord, and teeth (perivascular niche of dental pulp and periodontal ligament). MSCs are attractive for clinical therapy due to their ability to differentiate, provide trophic support, and modulate innate immune response. These cells differentiate into various cell types such as osteoblasts, chondroblasts, adipocytes, neuroectodermal cells, and hepatocytes.
Bioactive mediators that favor local cell growth are also secreted by MSCs. Anti-inflammatory effects on the local microenvironment, which promote tissue healing, are also observed. The inflammatory response can be modulated by adipose-derived regenerative cells (ADRC) including mesenchymal stem cells and regulatory T-lymphocytes. The mesenchymal stem cells thus alter the outcome of the immune response by changing the cytokine secretion of dendritic and T-cell subsets. This results in a shift from a pro-inflammatory environment to an anti-inflammatory or tolerant cell environment.
Endothelial stem cells
Endothelial stem cells are one of the three types of multipotent stem cells found in the bone marrow. They are a rare and controversial group with the ability to differentiate into endothelial cells, the cells that line blood vessels as well as lymphatic vessels. Endothelial stem cells are an important aspect of the vascular network, even influencing the motion relating to white blood cells.
Neural stem cells
The existence of stem cells in the adult brain has been postulated following the discovery that the process of neurogenesis, the birth of new neurons, continues into adulthood in rats. The presence of stem cells in the mature primate brain was first reported in 1967. It has since been shown that new neurons are generated in adult mice, songbirds, and primates, including humans. Normally, adult neurogenesis is restricted to two areas of the brain – the subventricular zone, which lines the lateral ventricles, and the dentate gyrus of the hippocampal formation. Although the generation of new neurons in the hippocampus is well established, the presence of true self-renewing stem cells there has been debated. Under certain circumstances, such as following tissue damage in ischemia, neurogenesis can be induced in other brain regions, including the neocortex.
Neural stem cells are commonly cultured in vitro as so-called neurospheres – floating heterogeneous aggregates of cells, containing a large proportion of stem cells. They can be propagated for extended periods and differentiated into both neuronal and glial cells, and therefore behave as stem cells. However, some recent studies suggest that this behavior is induced by the culture conditions in progenitor cells, the progeny of stem cell division that normally undergo a strictly limited number of replication cycles in vivo. Furthermore, neurosphere-derived cells do not behave as stem cells when transplanted back into the brain.
Neural stem cells share many properties with hematopoietic stem cells (HSCs). Remarkably, when injected into the blood, neurosphere-derived cells differentiate into various cell types of the immune system.
Olfactory adult stem cells