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Instability of Stem Cells
#1
Stem cells are the basic building blocks for many types of cells in the body. Despite the big therapeutic potential for stem cells to treat serious disorders, there are still concerns about potentially dangerous results. Researchers are excited about the possibilities of saving lives and reducing morbidity from disease, but there are also fears regarding unexpected results and effects from stem cell usage. With recent technologies the concept of stem cell therapies is no longer such a foreign one. The benefits of stem cell therapies are enormous, but risks must also be considered.

Embryonic Stem Cells

Main concern with embryonic stem cells is related to uncontrolled growth. Embryonic stem cells are cells which tend to grow fast. However, the rapidly growth must be carefully guided by researchers. These stem cells need to be cultivated and directed into specialised cells with great care because the potential for remaining stem cells to grow uncontrolled could be terrible. These uncontrolled stem cells could eventually form tumours. Embryonic stem cells division are subject to errors during cell division that can result in abnormal chromosome forms. Cytogenetics, the study of abnormal chromosomes, has shown that stem cells tend to show the chromosome aberrations. The most frequent change in human embryonic stem cells involves gain of chromosomes 12 or 17, which both are associated with cancer. There is no way to differentiate embryonic stem cells with abnormal chromosomes form and normal stem cells without genetic testing, because both express the same proteins and specifically stem cell markers. Additionally, the presence of chromosome changes does not affect the ability of these cells to different into appropriate cell types. However, most of these divisions lead to cell death, as a result accidents in division, which lead to extra or missing chromosomes.
Some researchers claim normal chromosomes in human embryonic cells after prolonged time in culture, even after 100 passages. Others have reported recurrent aberrations involving chromosomes 12 and 17 occurring between passages 25 and 45. Despite optimal culture techniques, the genetic integrity of embryonic stem cells is difficult to keep, because of the stresses of tissue culture and the other pressures exerted on the cells after cultures have been frozen and thawed. Cryopreserved embryonic stem cells tend to grow poorly after thawing. Some cells with a growth rate resulting from an extra chromosome 12 or 17 can increase in number and eventually overgrow the normal cells.

Adult Stem Cells

Unlike embryonic stem cells, which can give rise to any lineage, adult stem cells can only generate cells of a specific lineage. Adult stem cells are present in specialized tissues throughout the body, such as bone marrow or skin, and are capable of unlimited production of differentiated cells. For adult stem cells to be able to divide continuously, they must have an active telomerase gene, which is characteristic of all embryonic stem cells. The presence of the telomerase gene enables stem cells to maintain the integrity of the chromosomes throughout many cell divisions, whereas differentiated cells of the body do not have this gene and therefore can undergo only a limited number of divisions. There is a general belief that cancer cells derive from mutated adult stem cells because differentiated cells have a limited life-span and therefore cannot accumulate the necessary mutations for malignant transformation.

Most mutations in adult stem cells that give rise to cancer or leukemia tend to be lineage specific because certain changes will promote growth in one tissue, but not another. Chronic myeloid leukemia is example. Chronic myeloid leukemia is caused by specific chromosome mutations in a bone marrow stem cell. The normal stem cells in the bone marrow divide only when more blood cells are needed, and they become quiet as a result of continuous blood cell production by the mutated stem cells. This enables the abnormal stem cells populating the bone marrow to divide continuously. The mutation in chronic myeloid leukemia includes specific mutations between chromosomes 9 and 22, but this chromosome aberration has no effect in any other tissue because chromosome changes associated with cancer are lineage specific.

The fact that cultured adult stem cells can undergo tissue-specific chromosome changes associated with malignant diseases emphasizes the need to ensure that any adult stem cells used therapeutically, including reprogrammed cells, be monitored for genetic changes.

Examples

Scientists have tried embryonic stem cell transplantation in animal experimental models for stroke. Undifferentiated embryonic stem cells that were transplanted into the rat brain, migrated to the damaged area and differentiated into neurons along the border of the lesion. When the same cell line was transplanted into the mouse brain, the embryonic cells did not migrate but remained in one area to produce malignant carcinomas. Embryonic stem cells were undifferentiated or pre-differentiated in vitro to neural progenitor cells.

Mouse embryonic stem cells can differentiate into liver cells in culture. When mice were injected in the spleen with 9 day old cultures, the cells migrated to the liver and generated liver cells. However, when 9 day old and 15 day old cell cultures were injected directly into the mouse liver, there was a high incidence of tumor formation. The authors conclude that even in 15 day old cultures, undifferentiated embryonic stem cells can persist that are capable of forming tumors when transplanted.

Scientists still do not know so much about how stem cell differentiation is controlled. Further research will explain how cell signals operate to trigger cell differentiation. Current stem cell treatments may eventually become routine and regular therapies for serious disease. However, it's important that the safety of these therapies is evaluated and that caution is displayed before a therapy becomes accepted for use. This will allow full benefits of stem cell therapies for everyone.
#2
The steady experience of cells to endogenous and exogenous agents that inflict DNA damage requires active repair processes to get rid of potentially mutagenic events in stem cells leading to cancer. The similar agents menace early human embryos with DNA damage that can eventually lead to mutations, cancer, and birth imperfections. In vitro, human embryonic stem cells (HESCs) impulsively undergo events leading to genetic instability and mutations. All these three types of genetic complications can have similar links to malfunctions in DNA repair systems, but little information now exists for HESCs. Consequently, the first step in accepting the causes of HESC genetic instability is to understand which DNA repair systems are faulty. We shall investigate the basis for this phenomenon in HESCs by evaluating their capacity to either repair DNA or form mutations.

We can culture two HESC lines and contrast HESC repair and mutation formation to that of control cells. We can use a new technique which simplifies the production and use of the feeder cells that support the growth of the HESCs. Genetic stability can be tested for HESCs grown on conventional feeder cells, as well as those grown in feeder free culture. Three types of DNA repair assays can be used to monitor the genetic stability of the two HESC lines grown in these different ways. As a first assays, DNA molecules with dissimilar randomly-induced damage are transferred into HESCs, and DNA repair is followed by the re-establishment of the activity of a reporter protein that is coded for in the damaged DNA. As a second assay we shall introduce specific DNA damage at a unique site in DNA that is transferred to HESCs and repair is determined using a polymerase chain reaction-based technique.

Since aneuploidy is also recognized to be sourced by double-strand DNA breaks, one can use two other assays to evaluate capacity of HESCs to repair that type of damage. These experiments will point toward DNA repair pathways that eradicate DNA damage and cause genetic instability. The final endpoint for these first round experiments is the formation of mutations. To study this, one can modified an assay system so that it will function in normal human cells to monitor mutations which arise instinctively or those which are induced by various agents.

As a conclusion, these investigations can provide the basis for understanding genetic instability in HESCs that can direct cells to tumor. The employment of HESCs clinically will necessitate such knowledge. Additionally, these results will also yield information on susceptibility to mutations of cells early in embryo development from stem cells.
  

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