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Adult Stem Cells, the Therapy of the Future?

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Human stem cells have been wrapped in a veil of controversy even before they were isolated in 1998. From Princess to Presidents, there use has been looked down upon by public figures, but to scientist the possibilities seem almost endless. With a ban on embryonic stem cells scientist have had to find a way to continue this ground breaking work in a way the general population sees as more ethical. Since that time the stem cell research has led to the discovery of many types of adult stem cells, a greater understanding of how they work, and a means to possible therapies that may make some of the most debilitating diseases a thing of the past.

In 1949 experiments on irradiation of mice bone marrow, and attempted rescue techniques led researchers to find that injection of, or shielding of spleen cells could lead to recovery (Kondo, et al. 2003). This discovery, unbeknownst to the researchers at that time, has led to controversial ethical dilemmas, and the possibility of regenerating human tissue and organs which could save many lives, all from microscopic cells referred to as stem cells. The road to stem cell discovery did not happen overnight. In 1981 the first mouse stem cell line was isolated, and it took seven years to derive hamster, and another seven years to derive primate stem cells (Murnaghan, 2010). In 1998 two groups in the United States were able to isolate human embryonic stem (ES) cells. James Thomson and his group at the University of Wisconsin, developed the first human ES cell lines from inner cell mass of early embryos (Thomson, et al.,1998), and John Gearhart and his group were able to isolate human ES cell lines from fetal gonad tissue (Shamblott, et al., 1998), both of these cell lines were pluripotent stem cells lines.

Some important definitions to keep in mind while reading this paper are the major types of stem cells; "Totipotent - cells able to give rise to all embryonic somatic cells & germ cells, Pluripotent - can give rise to cells of the three germ layers (endoderm, mesoderm, & ectoderm), Multipotent - cells which produce cells of a particular lineage or closely related family." (Tsonis, 2007).

The process of understanding, isolating, and growing specific cells which could 'rescue' an animal after irradiation took many steps before stem cells. Embryonal carcinomas (EC) lines in mice were discovered by Leroy Stevens in 1953. This research greatly enhanced the field of developmental biology, however when the transition from laboratory animals to humans took place a large ethical controversy was quick to follow. The first cell lines were derived from embryos obtained from in vitro fertilization (IVF). Many in the public drew a perception that scientist were killing embryos to study the cells they were made of. This led to many nations to put into laws to stop deriving stem cells. Some European countries banned the research, and the Roman Catholic Church posted the official view of: one-cell stage onward the moral value of the embryo is equal to that of a newborn baby or an adult human being (McLaren, 2007). In the US, federal funding was not allowed to be used in the process of deriving new stem cell lines, and research could only be carried out on lines which were created prior to August 9, 2001 (McLaren, 2007).

With funding cut and no ability to derive new cell lines researchers found themselves not only

in an ethical dilemma, but a stand-still in research. Researchers quickly adapted to the ever changing political environment, by switching their attention to the previous discovery of multipotent adult stem cells which can be obtained from adult species, circumventing the ethical issues surrounding embryos to further the research. Though adult stem cells are multipotent, that is give rise only to cells of the same germ layer, finding a reliable source to fuel research and trails became the next step for scientist.

Adult stem cells were first recovered from mice bone marrow using a florescent activated cell sorter (FACS) to obtain highly specific populations. FACS can be used in conjunction with flow cytometry which measures cell's overall size, and nuclear density. When specific antibodies are attached to the cell with florescent proteins the FACS can separate these cells from the rest of the population. It was thought that the first isolated cells were tissue specific, and responsible for growth and maintenance of that specific tissue or organ (Clarke, & Frisen, 2001). This view was later challenged by the observation that when adult stem cells are placed in tissues other than their origins (but still within the same germ layer, and later in others), they acquire cell characteristics of those environments (Gritti, Vescovi, & Galli, 2002). The reason it is believed that stem cells do not grow into other cells tissues is due to the signals of surrounding cells in that tissue which help drive it to the proper differentiated cell type.

The ability of adult stem cells to differentiate, to a point, into different tissues led to further questions by developmental biologist into these cells whereabouts. Further studies show that the exact location of adult stem cell populations are not always in the exact anatomical position in mice, and later proven in humans as well. Stem cells have been shown to be located in micro niches within a tissue (Ting, et al., 2008), these niches are segregated more biochemically than anatomically for the surrounding tissue. The exact location could be identified by the expression of immunocytochemicals or PCR markers, and later identified by whole-genome messenger RNA expression phenotypes (Muller, et al., 2008). Though adult stem cells do not have quite the same range of plasticity of embryonic stem cells, their ability to transcend within their own germ line is very promising.

Some of the first types of adult stem cells which were isolated were from bone-marrow stem cells. There are two distinct populations of stem cells found in bone marrow; hematopoietic stem cells - responsible for all blood cell lineages (Clarek & Frisen, 2001) and mesenchymal stem cells also known as: skeletal stem cells, multipotent adult progenitor cells (MAPCs), or grafted bone marrow cells (BMCs). The original cells have been isolated from bone grafts from rodents; they are known to form all of the cell types found in the immune system as well other cells types such as bone, adipocytes, cardiac & skeletal muscle (Bonilla, et al., 2005). When placed in the appropriate conditions bone-marrow stem cell's ability to produce multiple cell types gave many scientist great hope of their future therapeutic possibilities. The original cells isolated from the rodents required special additives into the media for them to expand, such as leukemia inhibitory factor (LIF), however



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