Stem Cells of Renewing Cell Populations
Through a series of experiments, it was shown that ependymal cells divide slowly in vivo and give rise to a population of progenitor cells in the subventricular zone [ 47 ]. A different pattern of scattered BrdU-labeled cells was observed in the spinal cord, which suggested that ependymal cells along the central canal of the cord occasionally divide and give rise to nearby ependymal cells, but do not migrate away from the canal.
Collectively, the data suggest that CNS ependymal cells in adult rodents can function as stem cells.
The cells can self-renew, and most proliferate via asymmetrical division. Many of the CNS ependymal cells are not actively dividing quiescent , but they can be stimulated to do so in vitro with mitogens or in vivo in response to injury. After injury, the ependymal cells in the spinal cord only give rise to astrocytes, not to neurons. How and whether ependymal cells from the ventricular zone are related to other candidate populations of CNS stem cells, such as those identified in the hippocampus [ 34 ], is not known.
Are ventricular and subventricular zone CNS stem cells the same population? These studies and other leave open the question of whether cells that directly line the ventricles—those in the ventricular zone—or cells that are at least a layer removed from this zone—in the subventricular zone are the same population of CNS stem cells. A new study, based on the finding that they express different genes, confirms earlier reports that the ventricular and subventricular zone cell populations are distinct.
The new research utilizes a technique called representational difference analysis, together with cDNA microarray analysis, to monitor the patterns of gene expression in the complex tissue of the developing and postnatal mouse brain. All of these genes in the recent study were expressed in cultured neurospheres, as well as the ventricular zone, the subventricular zone, and a brain area outside those germinal zones. This analysis also revealed the expression of novel genes such as A16F10, which is similar to a gene in an embryonic cancer cell line.
A16F10 was expressed in neurospheres and at high levels in the subventricular zone, but not significantly in the ventricular zone.
Interestingly, several of the genes identified in cultured neurospheres were also expressed in hematopoietic cells, suggesting that neural stem cells and blood-forming cells may share aspects of their genetic programs or signaling systems [ 38 ]. This finding may help explain recent reports that CNS stem cells derived from mouse brain can give rise to hematopoietic cells after injection into irradiated mice [ 13 ].
The hippocampus is one of the oldest parts of the cerebral cortex, in evolutionary terms, and is thought to play an important role in certain forms of memory. The region of the hippocampus in which stem cells apparently exist in mouse and human brains is the subgranular zone of the dentate gyrus. The rest of the BrdU-labeled cells do not have a recognizable phenotype [ 90 ].
Interestingly, many, if not all the BrdU-labeled cells in the adult rodent hippocampus occur next to blood vessels [ 33 ]. In the human dentate gyrus, some BrdU-labeled cells express NeuN, neuron-specific enolase, or calbindin, all of which are neuronal markers. The labeled neuron-like cells resemble dentate gyrus granule cells, in terms of their morphology as they did in mice. The study involved autopsy material, obtained with family consent, from five cancer patients who had been injected with BrdU dissolved in saline prior to their death for diagnostic purposes. The patients ranged in age from 57 to 72 years.
The greatest number of BrdU-labeled cells were identified in the oldest patient, suggesting that new neuron formation in the hippocampus can continue late in life [ 27 ]. Not surprisingly, fetal stem cells are numerous in fetal tissues, where they are assumed to play an important role in the expansion and differentiation of all tissues of the developing organism. Depending on the developmental stage of an animal, fetal stem cells and precursor cells—which arise from stem cells—may make up the bulk of a tissue.
This is certainly true in the brain [ 48 ], although it has not been demonstrated experimentally in many tissues. It may seem obvious that the fetal brain contains stem cells that can generate all the types of neurons in the brain as well as astrocytes and oligodendrocytes, but it was not until fairly recently that the concept was proven experimentally. There has been a long-standing question as to whether or not the same cell type gives rise to both neurons and glia. In studies of the developing rodent brain, it has now been shown that all the major cell types in the fetal brain arise from a common population of progenitor cells [ 20 , 34 , 48 , 80 , ].
Neural stem cells in the mammalian fetal brain are concentrated in seven major areas: olfactory bulb, ependymal ventricular zone of the lateral ventricles which lie in the forebrain , subventricular zone next to the ependymal zone , hippocampus, spinal cord, cerebellum part of the hindbrain , and the cerebral cortex. Their number and pattern of development vary in different species. These cells appear to represent different stem cell populations, rather than a single population of stem cells that is dispersed in multiple sites.
The normal development of the brain depends not only on the proliferation and differentiation of these fetal stem cells, but also on a genetically programmed process of selective cell death called apoptosis [ 76 ]. Little is known about stem cells in the human fetal brain. In one study, however, investigators derived clonal cell lines from CNS stem cells isolated from the diencephalon and cortex of human fetuses, The study is unusual, not only because it involves human CNS stem cells obtained from fetal tissue, but also because the cells were used to generate clonal cell lines of CNS stem cells that generated neurons, astrocytes, and oligodendrocytes, as determined on the basis of expressed markers.
In a few experiments described as "preliminary," the human CNS stem cells were injected into the brains of immunosuppressed rats where they apparently differentiated into neuron-like cells or glial cells. Although most of the cells died, occasionally, single CNS stem cells survived, divided, and ultimately formed neurospheres after one to two weeks in culture.
The neurospheres could be dissociated and individual cells replated. The cells resumed proliferation and formed new neurospheres, thus establishing an in vitro system that like the system established for mouse CNS neurospheres could be maintained up to 2 years. Depending on the culture conditions, the cells in the neurospheres could be maintained in an undifferentiated dividing state in the presence of mitogen , or dissociated and induced to differentiate after the removal of mitogen and the addition of specific growth factors to the culture medium.
The neurons generated under these conditions expressed markers indicating they were GABAergic, [the major type of inhibitory neuron in the mammalian CNS responsive to the amino acid neurotransmitter, gammaaminobutyric acid GABA ].
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However, catecholamine-like cells that express tyrosine hydroxylase TH, a critical enzyme in the dopamine-synthesis pathway could be generated, if the culture conditions were altered to include different medium conditioned by a rat glioma line BB Thus, the report indicates that human CNS stem cells obtained from early fetuses can be maintained in vitro for a long time without differentiating, induced to differentiate into the three major lineages of the CNS and possibly two kinds of neurons, GABAergic and TH-positive , and engraft in rats in vivo [ ].
Neural crest cells differ markedly from fetal or adult neural stem cells. During fetal development, neural crest cells migrate from the sides of the neural tube as it closes. The cells differentiate into a range of tissues, not all of which are part of the nervous system [ 56 , 57 , 91 ].
Neural crest cells form the sympathetic and parasympathetic components of the peripheral nervous system PNS , including the network of nerves that innervate the heart and the gut, all the sensory ganglia groups of neurons that occur in pairs along the dorsal surface of the spinal cord , and Schwann cells , which like oligodendrocytes in the CNS make myelin in the PNS. The non-neural tissues that arise from the neural crest are diverse. They populate certain hormone-secreting glands—including the adrenal medulla and Type I cells in the carotid body—pigment cells of the skin melanocytes , cartilage and bone in the face and skull, and connective tissue in many parts of the body [ 76 ].
Thus, neural crest cells migrate far more extensively than other fetal neural stem cells during development, form mesenchymal tissues, most of which develop from embryonic mesoderm as well as the components of the CNS and PNS which arises from embryonic ectoderm. This close link, in neural crest development, between ectodermally derived tissues and mesodermally derived tissues accounts in part for the interest in neural crest cells as a kind of stem cell.
In fact, neural crest cells meet several criteria of stem cells. They can self-renew at least in the fetus and can differentiate into multiple cells types, which include cells derived from two of the three embryonic germ layers [ 76 ]. Recent studies indicate that neural crest cells persist late into gestation and can be isolated from E The cells incorporate BrdU, indicating that they are dividing in vivo. When transplanted into chick embryos, the rat neural crest cells develop into neurons and glia, an indication of their stem cell-like properties [ 67 ].
However, the ability of rat E At the earlier stage of development, the neural tube has formed, but neural crest cells have not yet migrated to their final destinations.
Neural crest cells from early developmental stages are more sensitive to bone morphogenetic protein 2 BMP2 signaling, which may help explain their greater differentiation potential [ ]. The notion that the bone marrow contains stem cells is not new.
One population of bone marrow cells, the hematopoietic stem cells HSCs , is responsible for forming all of the types of blood cells in the body. HSCs were recognized as a stem cells more than 40 years ago [ 9 , 99 ]. Bone marrow stromal cells—a mixed cell population that generates bone, cartilage, fat, fibrous connective tissue, and the reticular network that supports blood cell formation—were described shortly after the discovery of HSCs [ 30 , 32 , 73 ]. The mesenchymal stem cells of the bone marrow also give rise to these tissues, and may constitute the same population of cells as the bone marrow stromal cells [ 78 ].
Recently, a population of progenitor cells that differentiates into endothelial cells, a type of cell that lines the blood vessels, was isolated from circulating blood [ 8 ] and identified as originating in bone marrow [ 89 ]. Whether these endothelial progenitor cells, which resemble the angioblasts that give rise to blood vessels during embryonic development, represent a bona fide population of adult bone marrow stem cells remains uncertain.
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Thus, the bone marrow appears to contain three stem cell populations—hematopoietic stem cells, stromal cells, and possibly endothelial progenitor cells see Figure 4. Hematopoietic and Stromal Stem Cell Differentiation. Two more apparent stem cell types have been reported in circulating blood, but have not been shown to originate from the bone marrow.
One population, called pericytes, may be closely related to bone marrow stromal cells, although their origin remains elusive [ 12 ]. The second population of blood-born stem cells, which occur in four species of animals tested—guinea pigs, mice, rabbits, and humans—resemble stromal cells in that they can generate bone and fat [ 53 ].
Of all the cell types in the body, those that survive for the shortest period of time are blood cells and certain kinds of epithelial cells. For example, red blood cells erythrocytes , which lack a nucleus, live for approximately days in the bloodstream.
The life of an animal literally depends on the ability of these and other blood cells to be replenished continuously. This replenishment process occurs largely in the bone marrow, where HSCs reside, divide, and differentiate into all the blood cell types. Both HSCs and differentiated blood cells cycle from the bone marrow to the blood and back again, under the influence of a barrage of secreted factors that regulate cell proliferation, differentiation, and migration see Chapter 5.
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HSCs can reconstitute the hematopoietic system of mice that have been subjected to lethal doses of radiation to destroy their own hematopoietic systems. This test, the rescue of lethally irradiated mice, has become a standard by which other candidate stem cells are measured because it shows, without question, that HSCs can regenerate an entire tissue system—in this case, the blood [ 9 , 99 ].
HSCs were first proven to be blood-forming stem cells in a series of experiments in mice; similar blood-forming stem cells occur in humans. HSCs are defined by their ability to self-renew and to give rise to all the kinds of blood cells in the body. This means that a single HSC is capable of regenerating the entire hematopoietic system, although this has been demonstrated only a few times in mice [ 72 ]. Over the years, many combinations of surface markers have been used to identify, isolate, and purify HSCs derived from bone marrow and blood. Two kinds of HSCs have been defined.
Long-term HSCs proliferate for the lifetime of an animal. Short-term HSCs proliferate for a limited time, possibly a few months. Long-term HSCs have high levels of telomerase activity.
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Telomerase is an enzyme that helps maintain the length of the ends of chromosomes, called telomeres, by adding on nucleotides. Active telomerase is a characteristic of undifferentiated, dividing cells and cancer cells. Differentiated, human somatic cells do not show telomerase activity.
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In adult humans, HSCs occur in the bone marrow, blood, liver, and spleen, but are extremely rare in any of these tissues. In mice, only 1 in 10, to 15, bone marrow cells is a long-term HSC [ ]. Short-term HSCs differentiate into lymphoid and myeloid precursors, the two classes of precursors for the two major lineages of blood cells. Lymphoid precursors differentiate into T cells , B cells , and natural killer cells. The mechanisms and pathways that lead to their differentiation are still being investigated [ 1 , 2 ].
Myeloid precursors differentiate into monocytes and macrophages, neutrophils, eosinophils, basophils, megakaryocytes, and erythrocytes [ 3 ]. In vivo , bone marrow HSCs differentiate into mature, specialized blood cells that cycle constantly from the bone marrow to the blood, and back to the bone marrow [ 26 ]. A recent study showed that short-term HSCs are a heterogeneous population that differ significantly in terms of their ability to self-renew and repopulate the hematopoietic system [ 42 ]. Attempts to induce HSC to proliferate in vitro —on many substrates, including those intended to mimic conditions in the stroma—have frustrated scientists for many years.
Although HSCs proliferate readily in vivo , they usually differentiate or die in vitro [ 26 ].