Stem cells replicate, and can generate a variety of more specialized cell types as they multiply. They are plentiful in the early embryo but can be found in adult tissues that undergo cell replacement as a result of physiological turnover or injury.
A zygote, the product of the fusing of maternal egg cell and a paternal sperm cell, divides countless times and generates different cell types that comprise the entire human body. A zygote, as well as the eight cells created by its first three cell divisions, is each capable of developing into a complete human. Such cells are called totipotent. The total potency of the stem cells becomes limited with the division of the cells. The final result is that there is a transmission of the cells from a totipotent to a pluripotent condition. After 5 days a hollow ball of cells, called blas­tocyst, forms. Its outer layer will form the placenta, where­as the inner cells will form the tissues of the developing embryo and are called pluripotent embryonic stem cells. They are capable of forming most embryonic cell types, but not all the tissues required for the complete development of a human being. Along the developmental pathway, pluripotent stem cells become more specialized and committed to a single function, for example, muscle cells. This process of cellular specialization, controlled genetically from the nucleus of the cell, is differentiation. Partially differentiated stem cells persist in most adult tissues and are called multipotent stem cells. They can make a limited number of specialized cell types and their most important function is to replace fully differentiated cells that are lost by depletion and damage [7].
Embryonic Stem (ES) Cells. Embryonic stem cells are pluripotent stem cells, which can replicate themselves indefinitely and are therefore said to be “immortal”. The ES cells are generally collected from the inner cell mass of a blastocyst (an early embryo), can be programmed to become any cell of the body, and can also be kept proliferating indefinitely in a culture dish [8,9]. Their potential sources are embryos stored at fertility clinics that were not used for IVF, embryos created by IVF, cloned embryos created by the somatic cell nuclear transfer (SCNT) meth­od, otherwise called therapeutic cloning.
Adult Stem (AS) Cells. Adult stem cells are multi­potent stem cells present in most tissues and supply them with replacement cells throughout life. They replicate and can undergo multi-lineage differentiation. They can be isolated from adult tissue or organ, umbilical cord blood, central nervous system (CNS), a tissue thought to be capable of extremely limited self-repair [10,11]. Recently, it was found that some AS cells have pluripotent stem cell properties, and can be manipulated into making cells for other tissues and organs in the body, different from their tissue if origin [12,13].
Stem Cell Biology. While there is a lot of information about what stem cells can do, until recently, little was known about the molecular processes underlying pluri­potency of these cells. In the past few years, the master genes essential for stem cells, were discovered. They include Nanog, Oct4, and Sox2 that encode transcription factors that regulate gene expression [14,15].
Oct4 regulates cell fate in the early embryo. It is expressed in the inner cell mass (ICM) of the blastocyst and is downregulated upon differentiation of these cells into trophoblast cells. Sox2 and FoxD3 are essential for plurip­otency in embryos. In cultured ES cells Stat3 activation by the cytokine LIF (leukemia inhibitory factor) is required to sustain self-renewal. Maintenance of replicating mouse ES cells requires a combination of activated Stat3 and Oct4 expression. A divergent homeobox transcription factor named Nanog is expressed in ES cells. Nanog over­expression maintains ES cell replication independently of LIF/Stat3 activation. Nanog-deficient ES cells lose their pluripotency and begin to differentiate. These data suggest that Nanog in concert with Oct4 and Sox2 work to support stem cell pluripotency and self-renewal. Boyer et al. [15] analyzed by microarray technology the entire genome of a human ES cell, and identified the genes regulated by these three transcription factors. They activate certain genes essential for cell growth and repress a set of genes essential for embryonal development. When Nanog, Oct4, and Sox2 are inactivated, as the embryo begins to develop the repressed genes become activated and the stem cell becomes a differentiated cell [14-17].
Pax3 isessential for embryonic development of cells that make and store the pigments in the skin and hair. It is expressed in AS cells in the skin and directs them to become melanocytes but prevents them from complete differentiation. Pax3 is involved in some tumors, which adds more evidence to the stem cell origin of some cancers. If that is correct, stem cells in the skin could be the ones that turn into melanomas [18].
In general, stem cells can express a variety of genes and then select a few for continued expression as they differentiate into a specific cell type. Other genes, not needed for this tissue, are repressed upon differentiation.
Mutations occur all the time as cells grow. Inside the body, mutated cells are removed by the immune system, whereas in a culture dish, they can grow uncontrolled like a cancer. When cultured at length, human ES cells accrue changes in their genome. During analysis of nine early- and late-passage cultures of human ES cell lines for genetic aberrations, using oligonucleotide arrays containing roughly 115,000 single nucleotide polymorphisms, four late- passage lines were found that developed copy number changes, such as amplification of the entire long arm of chromosome 17. Aberrations in the coding region in mitochondrial DNA consisted of missense and nonsense mutations. All these data suggest that late-passage lines are not usable for therapy, but early-passage lines could prove useful [19].