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The ethical and moral debate over the use of stem cells has taken center stage over the past decade. Stem cells are of great medical interest, since they have the potential to develop into almost any type of cell in the body. Regenerative medicine focuses on the potential uses of stem cells in medicine and how they can provide effective treatment for a range of diseases.

Stem cells have the capacity to divide indefinitely to replenish other cells in the body. When a stem cell divides, each daughter cell can remain a stem cell or become a more specialized cell, such as a red blood cell, a muscle cell or a nerve cell. An increasing body of evidence also suggests that molecular pathways and properties associated with normal stem cells is relevant to cancer development [1].

There are two types of mammalian stem cells: embryonic stem cells, which are found in blastocysts (the mammalian embryo at the stage at which it is implanted into the wall of the uterus), and adult stem cells, which are found in adult tissues.

Stem cells are undifferentiated, meaning that they aren’t committed to becoming a specific kind of cell in the body. They are characterized by the ability to self-renew (remaining undifferentiated) and the capacity to differentiate into specialized cell types (termed potency). Potency specifies a stem cell’s differentiation potential.

There are four classes of stem cell potency:

• Totipotent: A totipotent stem cell is produced from the fusion of an egg and sperm cell and has the ability to become any kind of cell in the body. For a brief period, each cell division creates identical totipotent cells — any one of these cells could develop into a fetus if placed in a woman’s uterus. By the fourth day, the totipotent cells begin to specialize, forming a blastocyte, the type of cell that forms the outer layer of a blastocyst. These cells will go on to form the placenta and other supporting tissues of the uterus necessary for fetus development.

• Pluripotent: The inner cluster of cells in a blastocyst, called inner mass cells, are pluripotent. Pluripotent stem cells have the ability of to become any kind of cell in the body other than cells of the placenta or other supporting tissues of the uterus. Because of this, pluripotent cells cannot form a fetus if placed in a woman’s uterus. Embryonic stem cells are generally considered pluripotent.

• Multipotent: As pluripotent cells continue to specialize, they become cells that only lead to the development of specific tissues. Multipotent stem cells have the ability to form several cell types of a closely related family of cells and are generally referred to by their tissue origin, e.g. cardiac stem cells, neural stem cells, bone marrow stem cells. Multipotent cells function as a repair system for damaged tissue. Adult stem cells are multipotent stem cells.

• Unipotent: Unipotent stem cells have the ability to produce only one specialized cell type. Unipotent cells maintain the property of self-renewal, thus distinguishing them from non-stem cells.

Pluripotent stem cells can be derived from a number of sources, all of which are associated with moral issues:

1. Surplus embryos that are the by-product of in vitro fertilization
2. Embryos created in the lab from donated sperm and eggs
3. Embryos created through a cloning technique called somatic cell nuclear transfer
4. Embryos from aborted fetuses

Pluripotent stem cells can also be obtained from umbilical cord blood, placenta and amniotic fluid.

Although pluripotent stem cells have greater potential, multipotent adult stem cells are currently being used therapeutically. Adult stem cells can be found in many organs and tissues, including bone marrow, peripheral blood, brain, muscle, liver, skin and heart. Nevertheless, a number of limitations exist with adult stem cells [2]. Adult stem cells are found in small quantities in adult tissues and umbilical cord blood, raising doubt that they could be grown in clinically significant quantities. Additionally, adult stem cells have not been found for all tissues of the body, necessitating the use of pluripotent stem cells for the generation of certain tissue types. Since adult stem cells are multipotent, they cannot be induced to develop into any cell type, i.e. manipulated to differentiate into a specialized cell type different than their final tissue type.

For more information on stem cell research and current federal policy on embryonic stem cell research, see Research!America.

References

1. Lobo et al. The biology of cancer stem cells. Annu Rev Cell Dev Biol. 2007;23:675-99.
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2. Vats et al. Stem cells. Lancet. 2005 Aug 13-19;366(9485):592-602.
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In 2004, Korean investigators lead by Woo Suk Hwang at Seoul National University announced the creation of the world’s first human embryonic stem cell line generated by somatic cell nuclear transfer (SCNT), which involves the transfer of DNA, usually from a skin cell, into an egg cell that has had its DNA-containing nucleus removed. The work, published in the prominent journal Science, was retracted in 2006 amidst evidence that the researchers had falsified their data.

However, a study published online August 2nd, 2007, by the journal Cell Stem Cell reports that the Koreans unintentionally created the world’s first human embryonic stem cell derived by parthenogenesis, or virgin birth. Development is triggered spontaneously from the egg alone without the need for sperm fertilization.

Parthenogenesis is a natural phenomena that occurs in some insects, including aphids, honeybees and formicine ants, as well as some reptiles, including geckos, rock lizards and Komodo dragons. The process also occurs, though more rarely, in plants. There are no known cases of naturally occurring parthenogenesis in mammals because of imprinted genes. Imprinted genes are genes whose expression is determined by the parent that contributed them instead of following the usual rule of inheritance in which both copies of an inherited gene (one from the mother and one from the father) are equally expressed. In 1899, Jacques Loeb documented the first case of artificial parthenogenesis, treating sea urchin eggs with inorganic salt solutions to initiate embryonic development instead of the sperm of the male urchin [1].

In January 2007, researchers from the Harvard Stem Cell Institute analyzed patterns of genetic recombination in parthenogenetically derived mouse embryonic stem (ES) cell lines [2]. What they found was surprising: in contrast to ES cells produced by nuclear transfer, which are homozygous at most loci (meaning they contain two copies of the same form of a given gene at a specific location on a chromosome, referred to as an allele), parthenogenetically derived ES cells show predominant heterozygosity (meaning they have different alleles at a number of chromosomal locations) as a result of meiotic recombination. Meiosis is the process of cell division in sexually reproducing organisms that results in a reduction in the number of chromosomes in reproductive cells and leads to the production of gametes in animals (male gametes are sperm and female gametes are eggs) and spores in plants. Meiotic recombination, also known as crossing over, is a process of physical rearrangement occurring between two strands of DNA. A common event during meiosis, recombination leads to offspring that has different combinations of genes from their parents.

Researchers examined Hwang’s cell line using genome-wide single nucleotide polymorphism (SNP) analysis and found recombination patterns that are consistent with its derivation from a parthenogenetically derived embryo. SNP (pronounced “snip”) analysis identifies DNA sequence variations that occur when a single nucleotide - A, T, C, or G - in the genome is changed, producing different alleles. Common SNPs only have two alleles. For example, ATCGATCG and ATCAATCG represent two alleles: G and A. SNPs make up about 90% of all human genetic variation and occur every 100 to 300 bases along the 3-billion-base human genome [3]. These small variations in DNA sequence can have a significant impact on how individuals respond to disease, drugs and other therapies.

Parthenogenesis may provide a method for the generation of stem cells that are therapeutically valuable for women. Stem cells created by parthenogenesis don’t require cloning and won’t be rejected by the host immune system. However, concerns regarding safety and differentaion efficiency exist, as mouse parthenogenetic embryos are unable to complete full development due to the absense of paternally expressed imprinted genes, and tissues derived from parthenogenetic embryonic stem cells appear to have growth defects [4]. Further study is required to characterize the stem cells generated in the study. Nevertheless, parthenogenetically derived stem cells are another step closer to patient-specific, personalized medicine.

References

1. Jacques Loeb. On the nature of the process of fertilization and the artificial production of normal larvae (plutei) from the unfertilized eggs of the sea urchin. Am J Physiol 1899 3:135-138. Reprinted in Studies in General Physiology. Chicago: The University of Chicago Press, 1905. pp. 539-543.
2. Kim et al. Histocompatible embryonic stem cells by parthenogenesis. Science 2007 315, 482–486.
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3. SNP Fact Sheet. Human Genome Project Information.
4. Hernandez et al. Paternal and maternal genomes confer opposite effects on proliferation, cell-cycle length, senescence, and tumor formation. Proc. Natl. Acad. Sci. U. S. A. 2003 100, 13344–13349.
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Scientists at the Wake Forest University School of Medicine and Harvard School of Medicine report in the Journal of Nature Biotechnology that they have isolated stem cells from amniotic fluid [1]. Further, by introducing growth factors, they were able to get the anmiotic fluid-derived stem cells to differentiate (a concept from developmental biology describing the process by which cells acquire a “type”) into muscle, fat, bone, blood vessel, liver and nerve cells.

The anmiotic fluid-derived stem cells are pluripotent (meaning a stem cell that has the potential to differentiate into any of the three embryonic germ layers); the mesoderm, which develops into muscle, bone, blood and connective tissue; the endoderm, which develops into digestive organs and the lungs; and the ectoderm, which develops into nerves, skin and the nervous system.

Anmiotic fluid-derived stem cells have a number of advantages over embryonic stem cells:
(1) No embryo needs to be harmed in the harvesting of AFS cells
(2) AFS cells will not form tumor cells as embryo-derived cells do
(3) AFS cells are fast growing, doubling every 36 hours, and can thus be grown in large quantities
(4) Similar to embryonic stem cells, AFS cells have the potential of generating every type of adult cell

The work represents a giant step forward for stem cell research and raises the possibility that anmiotic fluid-derived stem cells will someday provide a valuable resource for tissue repair and engineered organs.

References

1. De Coppi et al. Isolation of amniotic stem cell lines with potential for therapy. Nat Biotechnol. 2007 Jan;25(1):100-6. Epub 2007 Jan 7.
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