Human Embryonic Stem Cells: Disease Treatment and Ethics

Introduction to Embryonic Stem Cells

Pluripotent stem cell cultures were first isolated in 1981 by Evans and Kaufman from mouse blastocysts. It was found that these cells were capable of self-renewal, with a long-term capacity to remain undifferentiated under certain culture conditions. Studies have highlighted the basic difference between stem cells and embryonic stem cells. Embryonic stem cells have the potential to differentiate into all three germ layers. These cells also have the capacity to proliferate in culture conditions in an undifferentiated state, and they typically disappear after differentiating into germ layers. For clinical purposes, the origin of human embryonic stem cells is the pre-implantation embryo. Stem cell lines have been derived from the inner cell mass of human blastocysts produced by in vitro fertilization. Studies have shown that human embryonic stem cells share the key properties of embryonic stem cells (Cai et al. 2007, p. 1229). These properties include derivation from the pre-implantation embryo, prolonged proliferation in culture in an undifferentiated state, and the capacity to form all three germ layers. In addition, human embryonic stem cells can maintain a diploid karyotype and exhibit higher telomerase activity when kept in culture for extended periods.

There are two main properties of embryonic stem cells: indefinite cell renewal and the ability to differentiate into one or more cell types. Successful studies and applications of murine embryonic stem cell research have paved the way for exploring the important applications of human embryonic stem cells. Several tissues in the human body depend on a pool of adult or somatic stem cells for maintenance. These tissues include the hematopoietic system, skin, gut, and parts of the central nervous system. Studies have shown that depletion of stem cell pools can lead to many diseases, including leukemia, lymphoma, and certain genetic defects. Other diseases involve tissue destruction in which the affected tissues cannot be revived by stem cell pools. These conditions include Type 1 diabetes, which arises from autoimmune destruction of pancreatic beta cells, and liver failure resulting from cirrhosis caused by toxins or infectious agents (Zou et al. 2009, p. 98). The main approach to treating these diseases is replacement of the stem cell pools in the body. Reports have highlighted the success of bone marrow transplants and direct organ transplants. Human embryonic stem cells can be triggered to differentiate into adult stem cells to replace the damaged stem cell pool, thereby regenerating damaged or diseased tissues and organs clinically (Lerou and Daley, 2005, p. 321). Organ transplantation has been less favored than stem cell replenishment because of immune barriers, where immunosuppression becomes necessary to prevent graft rejection (Gepstein, 2002, p. 869).

For proper clinical and medical usage of embryonic stem cells, it is important that the developmental pathways of tissues within an embryo are studied and understood. Many kinds of embryonic stem cells have been characterized, including insulin-secreting cells, neural tissue, cardiomyocytes, endothelial cells, hematopoietic cells, hepatocytes, and osteoblasts. Stem cells can therefore be used clinically to treat medical conditions affecting these tissues and cell types (Lindvall and Kokaia, 2006, p. 1095).

Derivation and Cardiac Applications of Human Embryonic Stem Cells

Derivation of Human Embryonic Stem Cells

It has been reported that cells in the mammalian embryo have the capacity to regenerate into any tissue type in the body. This property is termed pluripotency. After fertilization, at the blastocyst stage, a hollow sphere of cells forms with an outer cell layer and an inner cell mass. The outer cellular layer develops into the trophectoderm, giving rise to the placenta and other supporting tissues. All other tissues in the body are derived from the inner cell mass (Cai et al. 2007, p. 1231).

Generation of Cardiomyocytes from Human Embryonic Stem Cells

For clinical usage, various protocols have been developed to trigger the differentiation of human embryonic stem cells into specialized cardiomyocytes. Studies have shown that 5-aza-2'-deoxycytidine has a significant enhancing effect on the differentiation of human embryonic stem cells toward cardiomyocytes (Mummery et al. 2002, p. 2734). However, the cardiomyocytes obtained by these methods are typically immature, displaying properties and functions more characteristic of fetal cardiomyocytes. There is therefore a need to develop better protocols that can drive the differentiation of human embryonic stem cells toward mature, specialized cardiomyocytes rather than fetal or immature forms (Stojkovic et al. 2004, p. 260).

Purified Population of Cardiomyocytes

A second important consideration highlighted in the literature is that obtaining a purified population of engrafted heart cells requires protocols capable of generating pure rather than mixed cell populations. For clinical usage, purified cell populations are preferred for best results. In certain clinical conditions, for example, only specific types of cardiomyocytes are appropriate. In the case of myocardial infarction and chronic heart failure, ventricular cardiomyocytes are needed rather than the sinus-nodal type, because sinus-nodal cardiomyocytes are more arrhythmogenic and have been reported to cause morbidity in patients (Bhattacharya et al. 2004, p. 2959).

Use of Transgenes in Differentiated Cardiomyocytes

Human embryonic stem cells can generate differentiated heart cells under specific culture conditions, and these cells can be used for clinical purposes including treatment of heart failure and myocardial infarction. In some cases, previous studies have reported the use of transgenes. Reports have highlighted that transgenes can be a source of mutagenesis, negatively affecting cellular function. The only advantage of the transgenic approach is that it can help identify developmental pathways, enabling scientists to learn about culture conditions appropriate for cardiomyocyte development without relying on transgenes (Stojkovic et al. 2004, p. 263).

Use of Human Embryonic Stem Cells for Heart Conditions

In the Western world, ischemic heart disease is one of the leading causes of mortality. Within the heart, oxygen deprivation triggers irreversible cell damage, which can cause heart cell death. The damaged cells must be replaced by newer cells provided through cardiomyocyte transplantation. One of the main advantages of this approach is that permanent damage can be slowed as newer cells replace the lost ones (Cai et al. 2007, p. 1232).

Neurological Disorders and Stem Cell Therapy

Some of the most common neurological disorders include multiple sclerosis, Parkinson's disease, and stroke. These conditions are caused by the loss of neurons and glial cells. It is increasingly hoped that stem cells will provide a large and inexhaustible source of neurons and glia to support therapies aimed at cell replacement and neuroprotection. For this purpose, embryonic stem cells or fetal and adult stem cells from the central nervous system are considered the most suitable. For clinical applications, it is important that specific types of cells and neuroprotective molecules are used (Gepstein, 2002, p. 866).

Parkinson's Disease

Parkinson's disease is characterized by the gradual loss of nigrostriatal dopamine-containing neurons, though in some cases the loss of non-dopaminergic neurons has also been reported. The main symptoms of Parkinson's disease include reduced movement, rigidity, tremors, and increased postural instability. Current therapies include oral administration of L-Dopa along with dopamine receptor agonists (Lindvall and Kokaia, 2006, p. 1095). Another therapy involves deep brain stimulation of the subthalamic nucleus. While these treatments are effective for some symptoms, they cannot control the progression of the disease. There is therefore a need to find alternatives that can halt disease progression and offer a cure rather than simply managing symptoms. Significant improvements in mobility and long-lasting disease control are the goals that stem cell therapies aim to achieve (Bhattacharya et al. 2004, p. 2957).

Many clinical trials have transplanted fetal dopaminergic neurons to replace damaged dopaminergic neurons, with reports of major and long-lasting improvements in patients. Embryonic stem cells have shown the most promising results, demonstrating the capacity to regenerate into dopaminergic neurons. However, a great deal of further research is still needed to study the efficiency of stem cells in terms of striatal innervation, dopamine release, and relief from Parkinson's disease symptoms (Mummery et al. 2002, p. 2736).

Stroke

Strokes are caused by blockage of a cerebral artery, producing focal ischemia, loss of glial cells and neurons, and cognitive and sensory impairments. No current therapies can fully repair the damage caused by stroke, and even partial symptom relief is considered beneficial. Potential stem cell sources include fetal brain tissue, teratocarcinoma or neuroepithelial cell lines, umbilical cord, and bone marrow. These cells have demonstrated meaningful improvements in stroke-related conditions. Studies have also shown that these cells secrete trophic factors that play important roles in cell survival, proper cellular functioning, and regeneration. As a result, the cells can replace dead neurons, increase remyelination of axons, and repair damaged neuronal circuits (Barberi et al. 2006, p. 0555).

Huntington's Disease

Huntington's disease is a fatal disorder characterized by chorea — excessive spontaneous movements — as well as progressive dementia. The disorder is caused by the death of projection neurons in the striatum. When human embryonic stem cells are used clinically for the treatment of Huntington's disease, the main focus is on replacing striatal neurons. However, this therapeutic approach has been regarded as insufficient on its own, given that Huntington's disease is also associated with progressive neocortical degeneration. Functional recovery in patients has been promoted by replacing cells with grafts of fetal striatal neurons (Kehat et al. 2001, p. 412).

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is characterized by dysfunction and progressive degeneration of motor neurons at multiple locations, including the spinal cord, cerebral cortex, and brain stem. The disorder is marked by rapidly progressing muscle weakness, and death typically occurs within a few years of onset. For stem cell therapy to be effective in ALS, it is essential that stem cells replace both upper and lower motor neurons. The new neurons generated by the stem cells must also be able to integrate into neuronal circuitries. Various studies have investigated the possibility of generating lower motor neurons from stem cells — neurons capable of forming functional synapses with muscle fibers and extending their axons to the ventral roots following successful transplantation (Cai et al. 2007, p. 1237). This represents a long-term therapeutic approach.

A contrasting short-term approach focuses on preventing motor neurons from dying. Studies conducted in rats have shown that delivering human embryonic germ cells into the cerebrospinal fluid led to motor recovery, based on the migration of those cells into the spinal cord. These studies further highlighted that the efficiency of this process can be improved by genetically modifying stem cells to secrete molecules that promote neuron survival (Kehat et al. 2001, p. 407).

Conclusion

Human embryonic stem cells have been used in research aimed at curing a number of major diseases. These medical conditions include acute liver conditions, neurodegenerative conditions, and cardiac failure. Human embryonic stem cells have been studied as a means to regenerate and replace dying liver cells, malfunctioning neurons, and cardiomyocytes. A key property that underlies all of these applications is the cells' virtually infinite capacity to remain in an undifferentiated state until conditions are provided that direct them to differentiate into a specific cell or tissue type. Although stem cell research holds considerable therapeutic promise, it is accompanied by significant ethical concerns. Central among these are questions about the importance of human life at its earliest stage and whether new life should be sacrificed to preserve an already existing one.

References

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