Thursday, June 7, 2012

What are stem cells?


Structure and Functions

Stem cells are unspecialized cells that can develop into all the specialized cell types that organize themselves into the tissues, organs, and organ systems making up an entire individual. An egg fertilized by a sperm is called a totipotent stem cell, meaning that this single cell has the capacity to divide repeatedly and ultimately to contribute cells to each specialized body component. For example, from the single cell that is a fertilized human egg, cells must ultimately specialize to become the beating cells of the heart, pancreatic cells that produce insulin, skin cells that cover the body, and bone cells that support the body, among scores of other types of cells.



After fertilization, an egg divides repeatedly to form an embryo. The three- to five-day-old embryo is a hollow ball of cells called a blastocyst. Inside the blastocyst, a group of about thirty cells called the inner cell mass constitutes the stem cells of the embryo. Embryonic stem cells are referred to as pluripotent, because they have the capacity to develop into most, but not all, of the specialized cell types that will form the structures needed for the embryo to develop into an adult. Embryonic stem cells do not form the placenta, the structure that provides the essential connection between mother and embryo during gestation.


Adults also harbor several types of stem cells, although a very small number in each tissue. The major function of adult stem cells is to provide new cells to replenish aging or damaged ones. Many adult stem cells are believed to be sequestered in a specific area of tissue and remain nondividing until activated by tissue disease or injury. Others are required to provide new cells with greater frequency. For example, skin stem cells are constantly differentiating into mature skin cells to replace the large numbers of cells naturally lost each day.


Pluripotent hematopoietic (blood) stem cells reside in the bone marrow and are also very active. They regenerate themselves through mitosis but also divide into the numerous specialized cells found in the blood, including the red blood cells that carry oxygen, the various types of white blood cells involved in body defenses, and the platelets critical to clot formation.


Unlike specialized cells such as heart cells, brain cells, and muscle cells, which do not normally replicate themselves, stem cells may replicate many times, even when isolated from the body and propagated in the laboratory. Because of their capacity to regenerate themselves and their ability to differentiate into specific tissue types, scientists are isolating and studying stem cells in hopes of understanding diseases such as cancer. They are exploring the prospect of using stem cells as therapeutic agents in treating a host of diseases and disorders, including Parkinson’s disease, diabetes mellitus, and some forms of heart disease.


Embryonic stem cells are studied in the laboratory by isolating the inner cell mass from a three- to five-day-old embryo. The embryos are typically donated for research, with informed consent, by individuals who have extra, unneeded embryos created by in vitro fertilization for the treatment of infertility. The cells are added to a culture dish containing a nutrient medium and coated with mouse cells that provide a sticky surface to which the stem cells adhere. Newer methods allow stem cells to grow in the absence of contaminating mouse cells. The stem cells replicate repeatedly and fill the dish, then are divided and added to fresh culture dishes. After six months of repeated growth, division, and transfer to fresh culture dishes, the original thirty stem cells may yield millions of embryonic stem cells. The cells are analyzed at six months of growth, and if they have not differentiated, remain pluripotent, and appear genetically normal, then they are referred to as an embryonic stem-cell line.


Adult stem cells have proven to be much more difficult to grow in culture, and doing so has been a major focus of work by scientists. Unlike embryonic stem cells, adult stem cells are generally limited to differentiating into the cell type of their tissue of origin. Some evidence suggests, however, that certain types of adult stem cells may be manipulated in the laboratory to differentiate into a broader range of tissue types.




Medical Applications

There are three major areas of stem cell research, each with potential medical applications. One branch of research seeks to discover and understand the many steps in the complex process of cellular differentiation. Other researchers are exploring the potential uses of stem cells in pharmaceutical development. A third major line of research focuses on the use of stem cells in the treatment of a host of diseases.


Embryonic stem cells are used to study the processes by which undifferentiated stem cells differentiate into specialized cell types. Through this work, scientists will gain a greater understanding of normal cell development. Understanding the mechanisms of normal cell development will provide insights into situations of abnormal growth and development. Scientists already know that turning specific genes on and off at critical times in the differentiation process is what leads to one cell becoming a muscle cell, another a lung cell, and still another a red blood cell, but the signals that influence these genes are only partially understood. Many serious medical conditions, such as cancer and certain birth defects, are the result of abnormal cellular differentiation and division. A better understanding of these processes in normal situations could lead to major insights in the development of such disorders and perhaps point the way to preventive measures or new therapeutic tools.


Established cell lines are often used by pharmaceutical companies when testing potential products. For example, cancer cell lines are used to test antitumor drugs. If human stem cell lines were available, then many drugs could be tested for both beneficial and toxic effects in stem cell cultures in one of two general fashions. In one case, drugs could be tested for their effects, either positive or negative, on the normal differentiation of stem cells into specialized cells. In a second scenario, pluripotent stem cells could be used to create new lines of a variety of differentiated cell types that are not yet available, and drugs specific for that cell type could be tested on these cell cultures. In either case, screening drugs with cell lines derived from human stem cells would have the advantage of testing directly on human cells. Such testing would decrease the number of nonhuman animals used in drug testing and could decrease the number of human clinical trials needed to prove the efficacy and safety of a drug, thus speeding it through the governmental approval process and making it available to the public. To screen drugs effectively, however, the cells must be identical from culture to culture and for each drug being tested. To achieve this, scientists must understand the cellular signals and biochemical pathways that control cellular differentiation into the desired cell type so that the process can be controlled precisely in repeated experiments. Scientists do not yet understand differentiation well enough to initiate drug testing in stem cells, but many are working toward that goal.


Perhaps the most exciting area of stem cell research is the possibility of using pluripotent stem cells to treat disease. Organ and tissue transplantation is commonly used to treat a number of medical conditions. Heart and kidney transplants are a few examples. These treatments are available only when organs fail and often put the patient at serious risk of death. The donor material often must come from donation of the organs after the death of another individual. There are serious shortages of transplantable organs, and many patients die before suitable donor organs become available. Even if a transplant can be performed, the body will attack the transplanted organ because it is perceived as foreign, thus risking the destruction and rejection of the organ. Even with powerful drugs to suppress this response, some organs are still rejected, with dire consequences for the recipient.


Pluripotent stem cells, if directed to differentiate into specific cell types, have the potential to provide a renewable source of cells and tissue. For example, it may be possible to generate healthy heart cells from stem cells in the laboratory, then transplant these cells into a damaged heart. The hope is that the transplanted cells would proliferate and grow into healthy, functioning tissue that would rejuvenate the damaged heart and circumvent the need for heart transplantation. Other conditions that could be treated with stem cell therapy are diabetes, Alzheimer’s disease, Parkinson’s disease, stroke, burns, and spinal cord injury. Although a great deal of research is ongoing in this area of regenerative medicine, not all stem cell therapies are experimental. For example, transplantation of blood-forming hematopoietic stem cells found in bone marrow has been in use since the 1960s. More pure preparations of adult hematopoietic stem cells are currently approved for the treatment of leukemia, lymphoma, and several inherited blood disorders.




Perspective and Prospects

In the 1960s, researchers first discovered that bone marrow contains at least two types of stem cells. One type, termed hematopoietic stem cells, was found to form all of the different types of blood cells. The second line, termed stromal cells, generates fat, cartilage, and connective tissue. Also during this time, scientists studying adult rat brains discovered areas that contained undifferentiated cells that divided and differentiated into nerve cells. At that time, scientists did not believe that brain cells could regenerate themselves and discounted the results of this study. In the 1990s, enough evidence had accumulated for scientists to agree that adult brains, including those of humans, contain stem cells that are able to differentiate into the three major types of cells found in the mature brain. The two main neurogenic areas of the adult mammalian brain are now known to be the olfactory bulb, which controls the sense of smell, and the hippocampus, a memory center.


Much of what scientists know about stem cells and their differentiation has come from studies in mice. The first stem cells were isolated from mouse embryos in 1981. Scientists treated these cell lines with various growth factors to stimulate the development of a particular cell type. For example, cells treated with vitamin A derivative differentiated into nerve cells. All types of blood cells and cardiac cells have been generated in similar fashions, and in 2000 scientists from StemCells, Inc., produced mature liver cells from the hematopoietic stem cells of mice. That same year, neuroscientists at Johns Hopkins University announced that they had successfully reversed paralysis in rats and mice by injecting them with embryonic stem cells. The cells migrated to a region of the spinal cord that contains motor nerve cells. Half of the rats regained movement in their hind feet. This success was heralded as a first step toward curing human neurological disorders with stem cells.


While mice are excellent models for research on human biology, they are not human. Ideally, research would be conducted on human cells. Human pluripotent stem cells were isolated for the first time by scientists Michael Shamblott and James Thomson, working independently, in 1998. In 2000, scientists were successful in isolating stem cells from human cadavers and directing their development from bone marrow stem cells into nerve cells. In the late 1990s and the early twenty-first century, a body of research accumulated to indicate that adult stem cells exist in more body tissues than originally believed. This finding has led scientists to explore using adult stem cells, rather than embryonic stem cells, as sources of transplant material. In 2008, the first organ transplant using a patient’s own stem cells was successfully performed. A team of doctors in Barcelona, Spain, replaced a thirty-year-old woman's trachea using a donor trachea that had been stripped of living cells and seeded with stem cells from the woman’s bone marrow. This area of research took yet another step forward in 2011, when scientists crafted an artificial trachea out of glass and seeded it with stem cells from a patient into whom it was then implanted by doctors in Sweden. Use of adult stem cells has the advantage of the transplant material being from the recipient, so it is not rejected by the body as is a foreign transplant.


Some adult stem cells have been shown, under the right conditions, to differentiate into a variety of cells that are not the tissue from which they were derived. In April 2003, it was reported that fourteen patients with severe heart disease improved after being injected with stem cells harvested from their own bone marrow. Other studies suggest that stem cells derived from umbilical cord blood could be stored and provide a source of stem cells for therapeutic use at a later time.


In 2007, American and Japanese scientists created adult human stem cells from differentiated skin cells. The process used to achieve this involved taking adult skin cells and infecting them with several genes known to be highly active in embryonic stem cells but less active in differentiated cells. The cells, called induced pluripotent stem cells (iPS), are therefore reprogrammed into an embryonic state. In 2009, another group produced iPS from adult fat cells. This case is particularly exciting because there is no shortage of fat cells available for reprogramming. Essentially, each human is carrying a supply of potential stem cells. However, severe problems are associated with the efficiency of the reprogramming process, and there are also concerns that some of the genes used to create iPS could cause cancer. Intense research is being performed, and in the future, iPS technology could be used as a therapeutic tool.


Because of the small amounts, scarcity, and lower developmental potential of adult stem cells, scientists believe that they must experiment with cells derived from fetuses and embryos if stem cell research is to progress and fulfill the promise of therapy for a host of dread diseases. Because embryos must be destroyed in order to isolate stem cells, the use of embryonic stem cells is controversial, particularly within the United States. In 2001, President George W. Bush banned the use of federal funds for embryonic stem-cell research except for the sixty-four stem-cell lines in existence at the time. In 2006, Bush vetoed a bill that reversed his previous decision and allowed use of federal funds for embryonic stem-cell research. As of 2006, fewer than one-third of the original sixty-four embryonic stem-cell lines were being studied because most either acquired deleterious mutations or propagated poorly and were discontinued.


Great Britain instituted no such restrictions on stem cell research, and in September 2002, plans were unveiled for the United Kingdom Stem Cell Bank, to be located in Hertfordshire. It was to be the world’s first center for storing and supplying tissue from human embryos and aborted fetuses to be used to repair diseased and damaged tissues. Subsequently, in 2005, the National Stem Cell Bank (NSCB) was established in the United States at WiCell Research Institute in Madison, Wisconsin, to acquire, characterize, and distribute the twenty-one of the original sixty-four human embryonic stem-cell lines that have been approved for federal government funding.


In 2004, the unfavorable attitude toward embryonic stem-cell research started to change, and voters in California passed Proposition 71, the California Stem Cell Research and Cures Initiative, which authorizes the sale of bonds to allocate $3 billion over ten years to stem cell research, with priority given to studies examining human embryonic stem cells. The initiative allowed the formation of the California Institute for Regenerative Medicine (CIRM), a stem cell agency that oversees the direction of research and distributes funding.


In 2009, President Barack Obama overturned the ban on the use of federal funding for embryonic stem-cell research. Also, with a huge increase in funding to scientists, the United States can now be competitive in the fast-moving, exciting field of embryonic stem-cell research. This should open doors to the future use of embryonic stem cells or iPS to cure human diseases.




Bibliography


Barber, Lionel, and John Rennie, eds. The Future of Stem Cells. Spec. issue of Scientific American and Financial Times July 2005: A3–35. Print.



Board on Life Sciences, National Research Council, and Board on Health Sciences Policy, Institute of Medicine of the National Academies. Guidelines for Human Embryonic Stem Cell Research. Washington: Natl. Acads., 2005. Print.



Committee on the Biological and Biomedical Applications of Stem Cell Research, Commission on Life Sciences, National Research Council. Stem Cells and the Future of Regenerative Medicine. Washington: Natl. Acad., 2002. PDF file.



Holland, Suzanne, Karen Lebacqz, and Laurie Zoloth, eds. The Human Embryonic Stem Cell Debate: Science, Ethics, and Public Policy. Cambridge: MIT P, 2001. Print.



Lanza, Robert, and Anthony Atala, eds. Essentials of Stem Cell Biology. 3rd ed. San Diego: Academic, 2014. Print.



Liu, Yunying, et al. "Generation of Functional Organs from Stem Cells." Cell Regeneration 2.1 (2013): n. pag. Web. 27 Aug. 2014.



Reece, Jane B., et al. Campbell Biology. 10th ed. San Francisco: Cummings, 2014. Print.



"Stem Cell Information." National Institutes of Health. Natl. Insts. of Health, 4 Apr. 2013. Web. 27 Aug. 2014.

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