Faq
Introduction to Stem Cells
from ISSCR www.isscr.org
Where do stem cells come from?
Embryonic stem cells are derived from the inner cell mass of a blastocyst: the fertilized egg, called the zygote, divides and forms two cells; each of these cells divides again, and so on. Soon there is a hollow ball of about 150 cells called the blastocyst that contains two types of cells, the trophoblast and the inner cell mass. Embryonic stem cells are obtained from the inner cell mass.
Stem cells can also be found in small numbers in various tissues in the fetal and adult body. For example, blood stem cells are found in the bone marrow that give rise to all specialized blood cell types. Such tissue-specific stem cells have not yet been identified in all vital organs, and in some tissues like the brain, although stem cells exist, they are not very active, and thus do not readily respond to cell injury or damage.
Stem cells can also be obtained from other sources, for example, the umbilical cord of a newborn baby is a source of blood stem cells. Recently, scientists have also discovered the existence of cells in baby teeth and in amniotic fluid that may also have the potential to form multiple cell types. Research on these cells is at a very early stage.
Recently, cells with properties similar to embryonic stem cells, referred to as induced pluripotent stem cells (iPS cells) have been engineered from somatic cells (see ‘What is are induced pluripotent stem cells?’).
What is a stem cell line?
A stem cell line is a population of cells that can replicate themselves for long periods of time in vitro, meaning outside of the body. These cell lines are grown in incubators with specialized growth factor-containing media (liquid food source), at a temperature and oxygen/carbon dioxide mixture resembling that found in the mammalian body.
What is an embryonic stem cell?
Embryonic stem cells are those grown from the cells that make up the inner cell mass of the blastocyst. Embryonic stem cells have been derived from a variety of animals, including human, and are described as ‘pluripotent’- that is, they are capable of generating any and all cells in the body under the right conditions.
Embryonic stem cell lines can be grown indefinitely in vitro if the correct conditions are met. Importantly, these cells continue to retain their ability to form different, specialized cell types once they are removed from the conditions that keep them in an undifferentiated, or unspecialized, state.
The most widely studied are mouse embryonic stem cells. Mouse embryonic stem cells have taught us a lot about how pluripotent cells grow and specialize, and how embryonic development works. Indeed, mouse embryonic stem cells are a critical research tool for studying the function of individual genes and modeling human diseases. Mouse embryonic stem cells can be manipulated to contain specific genetic changes then used to generate mice which contain this change. Capecchi, Evans and Smithies were awarded the Nobel Prize in Physiology or Medicine, 2007 for developing this process. Read more.
Human embryonic stem cells were isolated relatively recently, in 1998. They are more difficult to work with than their mouse counterparts and currently less is known about them. However, scientists are making remarkable progress, learning about human developmental processes, modeling disease and establishing strategies that could ultimately lead to therapies to replace or restore damaged tissues using these human cells.
What is an adult (tissue-specific) stem cell?
Perhaps better referred to as a tissue-specific stem cell, these cells are found in tissues that have already developed. Tissue-specific stem cells can be isolated from many tissues, including brain. The most common source of tissue-specific stem cells is the bone marrow, located in the center of some bones. There are different types of stem cells found in the bone marrow, including hematopoietic or blood stem cells, endothelial stem cells, and mesenchymal stem cells. It is well established that hematopoietic stem cells form blood, that endothelial stem cells form the vascular system (arteries and veins), and that mesenchymal stem cells form bone, cartilage, muscle, fat, and fibroblasts.
While it has been theorized that some adult stem cells may have a broader potential to form different cell types than was previously suspected (for example, cells from the bone marrow may contribute to regeneration of damaged livers, hearts and other organs), this is highly controversial in the scientific community. Currently, it is not clear whether stem cells from adult tissues or umbilical cord blood are truly pluripotent. The comparison of human embryonic stem cells to adult stem cells is currently a very active area of research.
What are ‘induced pluripotent cells’ or iPS cells?
Induced pluripotent cells (iPS cells) are non-pluripotent cells that were engineered (‘induced’) to become pluripotent, that is, able to form all cell types of the body. In other words, a cell with a specialized function (for example a skin cell) was ‘reprogrammed’ to an unspecialized state similar to that of an embryonic stem cell. While iPS cells and embryonic stem cells share many characteristics they are not identical.
The generation of mouse iPS cells was reported in 2006 (read the ‘Briefing’ http://www.isscr.org/public/briefings/mouse_skin.htm), and the generation of human iPS cells at the end of 2007 (read the ‘Briefing’ http://www.isscr.org/public/briefings/breakthrough.html).
Currently, iPS cells are produced by inserting copies of three-four genes into specialized cells known to be important in embryonic stem cells using viruses. Different groups have used slightly different combinations of genes. It is not completely understood how each of these genes functions to confer pluripotency and ongoing research is addressing this question.
The technology used to generate iPS cells holds great promise for creating patient- and disease-specific cell lines for research purposes. However, a great deal of work remains before these methods can be used to generate stem cells suitable for safe and effective therapies.
What are the potential uses of human stem cells?
Stem cell research contributes to a fundamental understanding of how organisms develop and grow, and how tissues are maintained throughout adult life. This is knowledge that is required to work out what goes wrong during disease and injury and ultimately how these conditions might be treated. The development of a range of human tissue-specific and embryonic stem cell lines will provide researchers with the tools to model disease, test drugs and develop increasingly effective therapies.
Replacing diseased cells with healthy cells, a process called cell therapy, is a promising use of stem cells in the treatment of disease; this is similar to organ transplantation only the treatment consists of transplanting cells instead of organs. Currently, researchers are investigating the use of adult, fetal and embryonic stem cells as a resource for various, specialized cell types, such as nerve cells, muscle cells, blood cells and skin cells that can be used to treat various diseases.
In theory, any condition in which there is tissue degeneration can be a potential candidate for stem cell therapies, including Parkinson's disease, Huntington’s disease, spinal cord injury, stroke, burns, heart disease, Type 1 diabetes, osteoarthritis, rheumatoid arthritis, muscular dystrophies and liver diseases.
In addition, retinal regeneration with stem cells isolated from the eyes can lead to a possible cure for damaged or diseased eyes and may one day help reverse blindness. Bone marrow transplantation (transfers blood stem cells) is a well-established treatment for blood cancers and other blood disorders.
What are the obstacles that must be overcome before the potential uses of stem cells in cell therapy will be realized?
Here are just a few of the challenges that lie ahead. Firstly, a source of stem cells must be found. The process of identifying, isolating and growing the right kind of stem cell, for example a rare cell in the adult tissue, is painstaking. In general, embryonic and fetal stem cells are believed to be more versatile than tissue-specific stem cells. Secondly, once stem cells are identified and isolated, the right conditions must be developed so that the cells differentiate into the specialized cells required for a particular therapy. This too will require a great deal of experimentation. Thirdly, a system that delivers the cells to the right part of the body must be developed and the cells once there must be encouraged to integrate and function in concert with the body's natural cells. Furthermore, just as in organ transplants, the body's immune system must be suppressed to minimize the immune reaction set off by the transplanted cells.
While results from animal models are promising, the research on stem cells and their applications to treat various human diseases is still at a preliminary stage. As with any medical treatment, a rigorous research and testing process must be followed to ensure long-term efficacy and safety.
Are stem cells currently used in therapies today?
Hematopoietic stem cells (HSCs) or blood stem cells, present in the bone marrow are the precursors to all blood cells. Blood stem cells are currently the only type of stem cells commonly used for therapy. Doctors have been transferring blood stem cells by bone marrow transplant for more than 40 years. Advanced techniques for collecting or "harvesting" HSCs are now used to treat leukemia, lymphoma and several inherited blood disorders. Cord blood, like bone marrow, is stored as a source of HSCs and is being used experimentally as an alternative to bone marrow in transplantation.
New clinical applications for stem cells are currently being tested therapeutically for the treatment of musculoskeletal abnormalities, cardiac disease, liver disease, autoimmune and metabolic disorders (amyloidosis), chronic inflammatory diseases (lupus) and other advanced cancers. However, these new therapies have been offered only to a very limited number of patients.
Why are researchers interested in developing disease-specific or patient-specific pluripotent stem cells?
The development of patient-specific or disease-specific pluripotent stem cells has great therapeutic promise for three reasons. Firstly, these cells could provide a powerful new tool for studying the basis of human disease and for discovering new drugs. Secondly, the resulting embryonic stem cells could be developed into a needed cell type, and if transplanted into the original donor, would be recognized as 'self', thereby avoiding the problems of rejection and immunosuppression that occur with transplants from unrelated donors.
Can induced pluripotent cells replace research on embryonic stem cells?
No. The derivation of human induced pluripotent stem cells opens up exciting new areas of stem cell research, however, this technology is at a very early stage and many fundamental questions remain. While iPS cells and embryonic stem cells share many characteristics they are not identical. The similarities and differences are still being explored.
Research on human embryonic stem cells, somatic cell nuclear transfer and ‘adult’ or tissue-specific stem cells needs to continue in parallel. All are part of a research effort that seeks to expand our knowledge of how cells function, what fails in the disease process, and how the first stages of human development occur. It is this combined knowledge that will ultimately generate safe and effective therapies.
What is regenerative medicine?
The goal of regenerative medicine is to repair organs or tissues that are damaged by disease, aging or trauma, such that function is restored, or at least improved.
The term regenerative medicine is often used nowadays to describe medical treatments and research that use stem cells (either adult or embryonic) to restore the function of organs or tissues. This can be achieved in different ways; first, by administering stem cells, or specific cells that are derived from stem cells in the laboratory; or second, by administering drugs that coax stem cells that are already present in tissues to more efficiently repair the involved tissue.
What is bioethics?
Bioethics is the study of the moral and ethical issues in the fields of scientific research, medical treatment and, more generally, in the life sciences. With advancing technology come new and exciting insights into scientific processes and diseases; at the same time, new ethical issues arise.
ABOUT HUNTINGTON’S DISEASE:
From National Institute of Neurological Disorders and Stroke National Institute of Health
What is Huntington's Disease?
Huntington's disease (HD) results from genetically programmed degeneration of brain cells, called neurons, in certain areas of the brain. This degeneration causes uncontrolled movements, loss of intellectual faculties, and emotional disturbance. HD is a familial disease, passed from parent to child through a mutation in the normal gene. Each child of an HD parent has a 50-50 chance of inheriting the HD gene. If a child does not inherit the HD gene, he or she will not develop the disease and cannot pass it to subsequent generations. A person who inherits the HD gene will sooner or later develop the disease. Whether one child inherits the gene has no bearing on whether others will or will not inherit the gene. Some early symptoms of HD are mood swings, depression, irritability or trouble driving, learning new things, remembering a fact, or making a decision. As the disease progresses, concentration on intellectual tasks becomes increasingly difficult and the patient may have difficulty feeding himself or herself and swallowing. The rate of disease progression and the age of onset vary from person to person. A genetic test, coupled with a complete medical history and neurological and laboratory tests, helps physicians diagnose HD. Presymptomic testing is available for individuals who are at risk for carrying the HD gene. In 1 to 3 percent of individuals with HD, no family history of HD can be found.
Is there any treatment?
Physicians prescribe a number of medications to help control emotional and movement problems associated with HD. In August 2008 the U.S. Food and Drug Administration approved tetrabenazine to treat Huntington’s chorea (the involuntary writhing movements), making it the first drug approved for use in the United States to treat the disease. Most drugs used to treat the symptoms of HD have side effects such as fatigue, restlessness, or hyperexcitability. It is extremely important for people with HD to maintain physical fitness as much as possible, as individuals who exercise and keep active tend to do better than those who do not.
What is the prognosis?
At this time, there is no way to stop or reverse the course of HD. Now that the HD gene has been located, investigators are continuing to study the HD gene with an eye toward understanding how it causes disease in the human body.
What research is being done?
Scientific investigations using electronic and other technologies enable scientists to see what the defective gene does to various structures in the brain and how it affects the body's chemistry and metabolism. Laboratory animals are being bred in the hope of duplicating the clinical features of HD so that researchers can learn more about the symptoms and progression of HD. Investigators are implanting fetal tissue in rodents and nonhuman primates with the hope of understanding, restoring, or replacing functions typically lost by neuronal degeneration in individuals with HD. Related areas of investigation include excitotoxicity (over-stimulation of cells by natural chemicals found in the brain), defective energy metabolism (a defect in the mitochondria), oxidative stress (normal metabolic activity in the brain that produces toxic compounds called free radicals), tropic factors (natural chemical substances found in the human body that may protect against cell death).
ABOUT PARKINSON’S DISEASE:
From National Institute of Neurological Disorders and Stroke
National Institute of Health
What is Parkinson's Disease?
Parkinson's disease (PD) belongs to a group of conditions called motor system disorders, which are the result of the loss of dopamine-producing brain cells. The four primary symptoms of PD are tremor, or trembling in hands, arms, legs, jaw, and face; rigidity, or stiffness of the limbs and trunk; bradykinesia, or slowness of movement; and postural instability, or impaired balance and coordination. As these symptoms become more pronounced, patients may have difficulty walking, talking, or completing other simple tasks. PD usually affects people over the age of 50. Early symptoms of PD are subtle and occur gradually. In some people the disease progresses more quickly than in others. As the disease progresses, the shaking, or tremor, which affects the majority of PD patients may begin to interfere with daily activities. Other symptoms may include depression and other emotional changes; difficulty in swallowing, chewing, and speaking; urinary problems or constipation; skin problems; and sleep disruptions. There are currently no blood or laboratory tests that have been proven to help in diagnosing sporadic PD. Therefore the diagnosis is based on medical history and a neurological examination. The disease can be difficult to diagnose accurately. Doctors may sometimes request brain scans or laboratory tests in order to rule out other diseases.
Is there any treatment?
At present, there is no cure for PD, but a variety of medications provide dramatic relief from the symptoms. Usually, patients are given levodopa combined with carbidopa . Carbidopa delays the conversion of levodopa into dopamine until it reaches the brain. Nerve cells can use levodopa to make dopamine and replenish the brain's dwindling supply. Although levodopa helps at least three-quarters of parkinsonian cases, not all symptoms respond equally to the drug. Bradykinesia and rigidity respond best, while tremor may be only marginally reduced. Problems with balance and other symptoms may not be alleviated at all. Anticholinergics may help control tremor and rigidity. Other drugs, such as bromocriptine, pramipexole, and ropinirole, mimic the role of dopamine in the brain, causing the neurons to react as they would to dopamine. An antiviral drug, amantadine, also appears to reduce symptoms. In May 2006, the FDA approved rasagiline to be used along with levodopa for patients with advanced PD or as a single-drug treatment for early PD.
In some cases, surgery may be appropriate if the disease doesn't respond to drugs. A therapy called deep brain stimulation (DBS) has now been approved by the U.S. Food and Drug Administration. In DBS, electrodes are implanted into the brain and connected to a small electrical device called a pulse generator that can be externally programmed. DBS can reduce the need for levodopa and related drugs, which in turn decreases the involuntary movements called dyskinesias that are a common side effect of levodopa. It also helps to alleviate fluctuations of symptoms and to reduce tremors, slowness of movements, and gait problems. DBS requires careful programming of the stimulator device in order to work correctly.
What is the prognosis?
PD is both chronic, meaning it persists over a long period of time, and progressive, meaning its symptoms grow worse over time. Although some people become severely disabled, others experience only minor motor disruptions. Tremor is the major symptom for some patients, while for others tremor is only a minor complaint and other symptoms are more troublesome. No one can predict which symptoms will affect an individual patient, and the intensity of the symptoms also varies from person to person.
What research is being done?
The National Institute of Neurological Disorders and Stroke (NINDS) conducts PD research in laboratories at the National Institutes of Health (NIH) and also supports additional research through grants to major medical institutions across the country. Current research programs funded by the NINDS are using animal models to study how the disease progresses and to develop new drug therapies. Scientists looking for the cause of PD continue to search for possible environmental factors, such as toxins, that may trigger the disorder, and study genetic factors to determine how defective genes play a role. Other scientists are working to develop new protective drugs that can delay, prevent, or reverse the disease.
From The Parkinson’s Institute
Stem Cell Breakthroughs: What Do They Mean for Parkinson’s?
Stem cells are often touted for the potential they hold to treat diseases, including Parkinson’s disease (PD). So, when a new development in stem cell science is referred to as a ‘breakthrough,’ you may wonder what the true implications are for PD treatments.
Since the last issue of News & Review, two studies have been published, each highlighting an alternative source of stem cells. In November 2007, scientists announced they had created stem cells by reprogramming human adult skin cells. More recently, on January 17, researchers at the Stemagen Corporation announced they had been successful in using adult skin cells to clone embryos.
What do these results truly mean for research funding, for governmental policy and, most importantly, for the development of treatments that may affect people living with PD?
Why are Stem Cells Important?
Researchers see promise in stem cells because of their ability to become any type of cell in the body. They foresee manipulating stem cells to create specialized cells that may be used to replace the cells or tissue damaged or destroyed by disease — such as the unhealthy or missing cells that are found in diseases such as Parkinson’s, diabetes, and Alzheimer’s.
In the case of Parkinson’s, this would entail manipulating stem cells into dopamine-producing neurons and using these to replace the cells that are lost in PD.
Prior to these recent developments, scientists looked to human embryonic stem cells (hESCs) as the most ideal type of stem cells for disease research and treatment development because they are the most versatile of stem cells. This is both because their structure allows them to transform into any type of tissue in the body and because they can be easily multiplied. The ability to multiply allows researchers to develop stem cell lines, groups of cells that make research much easier to perform.
Conversely, neither adult stem cells nor stem cells derived from cord blood have these abilities. Stem cells from these sources are more difficult to study and to translate into treatments.
Stem Cells Derived from Skin Cells
In November 2007, reports published in the prestigious journals Science and Cell, led respectively by Dr. Junying Yu, working in the lab of stem-cell pioneer Dr. James Thomson of the University of Wisconsin-Madison, and Dr. Shinya Yamanaka of Kyoto University, announced the successful creation of stem cells through the manipulation of human adult skin cells. With these accomplishments, both teams have created the first stem cells that have the same potential as human embryonic stem cells, but which do not require the use of human embryos.
Why is This a Breakthrough and What Does It Mean for Disease Treatments?
Scientifically, skin-derived cells are important because they hold potential similar to that of hESCs. That is, they are easily replicated and they have the ability to develop into any type of cell in the body. Therefore, skin-derived stem cells hold the potential to develop into cell replacement and tissue therapies — the same treatments that researchers have hoped to develop from hESCs.
Since skin-derived cells can be taken from adults who have a particular disease, they also open up the possibility of growing replacement tissue in a lab that is unique to the person who is being treated. Having a customized therapy of this kind could eliminate the concern about immune system rejection that comes with hESCs.
The discovery of skin-derived stem cells will have political and financial ramifications as well. Because the source of these cells is something other than a human embryo, the research will not be subject to the same constraints that were set by President Bush in 2001 for hESCs. These regulations limit federal funding for human embryonic stem cell research to lines developed before August 9, 2001. The rules essentially require institutions to house stem cell research in separate facilities, using separate equipment, from research funded by the government — creating a burden for institutions in terms of cost, logistics and liability. This problem was compounded by the fact that the available stem cell lines turned out to be many fewer than was originally thought and not always of the high quality necessary for research. Such issues have discouraged institutions and researchers from entering the field.
However, because stem cells derived from skin cells do not involve embryos, they bypass all of these regulations, meaning they will be eligible to receive federal funding. In fact, the President has already moved to encourage funding of research involving skin-derived cells, as evidenced by his statement in the State of the Union Address on January 28.
With the possibility of increased funding present and the belief of scientists that skin-derived stem cells can be easily and quickly replicated at institutions across the country, it is hoped that the sheer increase in the amount of research that can be performed will speed scientific progress.
What Scientific Barriers Still Exist in Developing Treatments?
While skin-derived stem cells appear to offer the same flexibility and potential as hESCs, they also possess some of the same inherent limitations as their predecessors, along with some new ones.
For instance, when hESCs are developed into treatments, they are able to transform again within the body. In cases where this proliferation is uncontrolled, the result can be the development of tumors (known as teratomas) in people being treated with stem cell therapies. Scientists have not yet figured out how to prevent this from happening, whatever the source of the stem cells.
In addition, skin-derived stem cells cannot be used as actual treatments as they currently exist because the process that transforms them into stem cells involves injecting them with viruses that could be harmful to patients.
Scientists Use Adult Skin Cells to Create Cloned Embryos
On January 17, researchers from Stemagen Corporation led by Andrew French, Ph.D., published a study in Stem Cells announcing that they had created five human embryo-like structures and brought them to the blastocyst stage by using somatic cell nuclear transfer (SCNT) — also known as therapeutic cloning.
These results represent the first time that a research team has brought a cloned embryo to the blastocyst stage. This is the point at which stem cells can be produced, although this study did not proceed far enough to do so.
Why is This a Breakthrough and What Does It Mean For Disease Treatments?
Because the study did not yet produce stem cells, its findings do not mean that the development of treatments is right around the corner. However, the approach is certainly promising.
The team, using the SCNT technique, took adult skin cells from two of the researchers and eggs (oocytes) donated from women who were undergoing fertility treatments at a nearby clinic. Following SCNT protocol, researchers removed the nuclei from adult skins cells and placed them within the donated eggs, whose own nuclei (and therefore, DNA) had been removed.
Through the use of this technology, the scientists were able to manipulate the eggs into becoming embryos containing the genetic material of the adult skins cells. Out of 25 eggs, researchers produced three blastocysts that were proven to be clones, meaning the blastocysts genetically matched the parent cells taken from the researchers.
If stem cells had been developed using this process, then, like skin-derived stem cells, they would have had the potential to lead to cell replacement and tissue therapies. Moreover, because the cells produced in this way would be genetically-matched to the donor, they could potentially be used as personalized treatments for diseases like Parkinson’s.
Researchers hope to one day use SCNT technology — taking body cells from an individual with a disease along with donated eggs — to create an embryo-like structure that carries a person’s own DNA. Unlike cells derived from other sources, the stem cells created from SCNT would be recognized as ‘self’ not as something for the immune system to attack.
What Scientific Barriers Still Exist in Developing Treatments?
Before proceeding to the development of treatments, researchers must first go one step further by yielding actual stem cells from the blastocyst stage and subsequently growing them into lines to be studied. Developing the stem cells into treatments for Parkinson’s will require further investigation. In addition, the health of the embryos created in the study will need to be assessed and verified by outside groups.
Conclusions
Overall, while important scientific challenges continue to exist with respect to stem cells derived from skin cells and from therapeutic cloning, these newly-discovered technologies provide the opportunity for researchers and institutions to explore more deeply the potential of stem cells to cure human diseases.
Although this research is exciting, scientists emphasize that studies involving human embryonic stem cells should continue in tandem with new techniques. Together, further research on stem cells from all sources will speed our understanding of disease and of possible treatments.
