Stem Cells
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Introduction •
A stem cell is a special kind of cell that has a unique capacity to renew itself and to give rise to specialized cell types. Although most cells of the body, such as heart cells or skin cells, are committed to conduct a specific function, a stem cell is uncommitted and remains uncommitted, until it receives a signal to develop into a specialized cells
•
In 1998, for the first time, investigators were able to isolate this class of pluripotent stem cell from early human embryos and grow them in culture.At about the same time as scientists were beginning to explore human pluripotent stem cells from embryos and fetal tissue, a flurry of new information was emerging about a class of stem cells that have been in clinical use for years—so-called adult stem cells. An adult stem cell is an undifferentiated cell that is found in a differentiated (specialized) tissue in the adult, such as blood. It can yield the specialized cell types of the tissue from which it originated. In the body, it too, can renew itself
•
The one-cell embryo develops into a fully formed human being through a process called cell differentiation. As an embryo develops, embryonic stem cells form the different cells that make up our bodies. As they go further along the developmental pathway, they become more and more specialised until they are only able to perform one function..
•
To be able to harness the therapeutic potential of stem cells, scientists need to learn how to direct them to differentiate appropriately, for example, to generate muscle cells for damaged hearts or neurones for damaged brains. Another challenge is to ensure they do not continue to multiply in an uncontrolled way and not form a tumour.
•
Current science indicates that, although both of these cell types hold enormous promise, adult and embryonic stem cells differ in important ways. What is not known is the extent to which these different cell types will be useful for the development of cell-based therapies to treat disease.
What Are Stem Cells? Stem cells are found in a number of areas of the body and occur at the earliest stages of human development through to adulthood. Whether they come from an early embryo, a fetus or an adult, stem cells have two key properties. : Firstly, they have the ability to reproduce themselves almost indefinitely through cell division. (Self renewal). Secondly, Regulated by intrinsic signals and the external microenvironment .they can be directed to generate cells with special functions that make up the tissues and organs of the body, such as the beating cells of the heart or the insulin-producing cells of the pancreas (unlimited potency). This capacity to both proliferate and form different types of cells makes them ideal for replacing tissue that is lost. They are 'all-purpose' cells.
Classification of Stem cells Stem cells are classified on the basis of 1. The extent to which they can differentiate into different cell types, 2. Source of stem cells.
Extent to which they can differentiate into different cell types: Stem cells are cells that divide by mitosis to form two stem cells, thus increasing the size of the stem cell "pool", - One daughter that goes on to differentiate, and - Another daughter that retains its stem-cell properties.
Pluripotent, embryonic stem cells originate as inner mass cells with in a blastocyst. The stem cells can become any tissue in the body, excluding a placenta. Only the morula's cells are totipotent, able to become all tissues and a placenta.
1. Totipotent cells. In mammals, totipotent cells have the potential to become o
Any type in the adult body;
o
Any cell of the extra-embryonic membranes (i.e., placenta).
The only totipotent cells are the fertilized egg and the first 4 or so cells produced by its cleavage (as shown by the ability of mammals to produce identical twins, triplets, etc.). 2. Pluripotent stem cells. These are true stem cells, with the potential to make any differentiated cell in the body (but probably not all those of the extra-embryonic membranes, which are derived from the trophoblast).
Three types of pluripotent stem cells have been found o
Embryonic Stem (ES) Cells. These can be isolated from the inner cell mass (ICM)
of the blastocyst — the stage of embryonic development when implantation occurs. For humans, excess embryos produced during in vitro fertilization (IVF) procedures are used. Harvesting ES cells from human blastocysts is controversial because it destroys the embryo, which could have been implanted to produce another baby (but often was simply going to be discarded). o
Embryonic Germ (EG) Cells. These can be isolated from the precursor to the
gonads in aborted fetuses. . o
Embryonic Carcinoma (EC) Cells. These can be isolated from teratocarcinomas, a
tumor that occasionally occurs in a gonad of a fetus. Unlike the other two, they are usually aneuploid. All three of these types of pluripotent stem cells - can only be isolated from embryonic or fetal tissue; - can be grown in culture, but only with special methods to prevent them from differentiating.
3. Multipotent stem cells These are true stem cells but can only differentiate into a limited number of types. For example, the bone marrow contains multipotent stem cells that give rise to all the cells of the blood but not to other types of cells. Multipotent stem cells are found in adult animals; perhaps most organs in the body (e.g., brain, liver) contain them where they can replace dead or damaged cells. These adult stem cells may also be the cells that — when one accumulates sufficient mutations — produce a clone of cancer cells.
On the basis of source: 1. Embryonic stem cells 2. Embryonic germ cells 3. Adult stem cells
1. Embryonic stem cells (ESCs) are derived from 4- to 5-day-old embryos. At this stage, the embryos are spherical and are known as blastocysts. Each blastocyst consists of 50 to 150 cells and includes three structures: an outer layer of cells, a fluid-filled cavity, and a group of about 30 pluripotent cells at one end of the cavity, called the inner cell mass.
Properties of an Embryonic Stem Cell Derived from the inner cell mass/epiblast of the blastocyst. Can be induced to continue proliferating or to differentiate. Clonogenic i.e. a single ES cell can give rise to a colony of genetically identical cells, or clones, which have the same properties as the original cell. Exhibit and maintain a stable, full (diploid), normal complement of chromosomes (karyotype). Pluripotent ES cells can give rise to differentiated cell types that are derived from all three primary germ layers of the embryo (endoderm, mesoderm, and ectoderm).
2. Embryonic (or fetal) germ cells Embryonic germ cells are pluripotent stem cells derived from so-called primordial germ cells, which are the cells that give rise to the gametes (sperm and eggs) in adults. Scientists obtain primordial germ cells from the area in a 5- to 9-week-old embryo/fetus destined to become either the testicles or the ovaries (the dividing line between embryo and fetus is the end of the 8th week).
Like ESCs, the primordial germ cells are transferred into a specially treated plastic culture dish, where they form germ cell colonies.
Less research has been performed using embryonic germ (EG) cells than ESCs, mostly because the embryos used for deriving EG cells are deliberately aborted, while the blastocysts used for deriving ESCs are produced through in vitro fertilization in a fertility clinic. EG cells are also difficult to maintain in cell culture because they have a tendency to differentiate spontaneously.
Factors required for maintaining Pluripotency •
Leukaemia inhibitory factor ( LIF )
•
Neuropoeitic and haematopoietic cytokine
•
Interleukin 6 family of cytokine receptors
•
Receptors associated with tyrosine kinase - JAK
•
Activate the STAT family of transcription factors
•
Signal Transducer and Activator of Transcription
3. Adult stem cells These cells share at least two characteristics. •
First, they can make identical copies of themselves for long periods of time; this ability to proliferate is referred to as long-term self-renewal.
•
Second, they can give rise to mature cell types that have characteristic morphologies (shapes) and specialized functions.
However, they are also found in children and can be extracted from umbilical cord blood.
The primary roles of adult stem cells in the body are to maintain and repair the tissues in which they are found. They are usually thought of as multipotent cells, giving rise to a closely related family of cells within the tissue.
A potential advantage of using adult stem cells from a patient is that the patient’s own cells could be expanded in culture, treated to differentiate into the desired cells, and then reintroduced into the patient.
The use of the patient’s own cells would eliminate any possibility that they might be rejected by the immune system.
Disadvantages of using adult stem cells are that they are rare in mature tissues and it is more difficult to expand their numbers in cell culture, compared with ESCs.
Differentiation
Adult stem cell differentiation
Figure 2. Hematopoietic and stromal stem cell differentiation. Click here for larger image. As indicated above, scientists have reported that adult stem cells occur in many tissues and that they enter normal differentiation pathways to form the specialized cell types of the tissue in which they reside. Adult stem cells may also exhibit the ability to form specialized cell types of other tissues, which is known as transdifferentiation or plasticity.The following are examples of differentiation pathways of adult stem cells (Figure 2). Hematopoietic stem cells give rise to all the types of blood cells: red blood cells, B lymphocytes, T lymphocytes, natural killer cells, neutrophils, basophils, eosinophils, monocytes, macrophages, and platelets.
Bone marrow stromal cells (mesenchymal stem cells) give rise to a variety of cell types: bone cells (osteocytes), cartilage cells (chondrocytes), fat cells (adipocytes), and other kinds of connective tissue cells such as those in tendons. neural stem cells in the brain give rise to its three major cell types: nerve cells (neurons) and two categories of non-neuronal cells—astrocytes and oligodendrocytes. Epithelial stem cells in the lining of the digestive tract occur in deep crypts and give rise to several cell types: absorptive cells, goblet cells, Paneth cells, and enteroendocrine cells. Skin stem cells occur in the basal layer of the epidermis and at the base of hair follicles. The epidermal stem cells give rise to keratinocytes, which migrate to the surface of the skin and form a protective layer. The follicular stem cells can give rise to both the hair follicle and to the epidermis. Hematopoietic stem cells may differentiate into: three major types of brain cells (neurons, oligodendrocytes, and astrocytes); skeletal muscle cells; cardiac muscle cells; and liver cells. Bone marrow stromal cells may differentiate into: cardiac muscle cells and skeletal muscle cells. Brain stem cells may differentiate into: blood cells and skeletal muscle cells.
Markers used to distinguish between pluripotent stem cells and their differentiated derivatives •
•
Cell-surface markers recognized by monoclonal antibodies o
Stage-specific embryonic antigens
o
Tumour-recognition antigens
Oct 4 o
POU-domain transcription factor
o
Differentiation associated with down-regulation of Oct4 levels
o
Downregulation of the Oct4 gene results in differentiation and loss of
pluripotent cells
Figure E.i.1. Identifying Cell Surface Markers Using Fluorescent Tags
Pluripotency tested in three independent assays 1. Able to differentiate in vitro in a Petri dish 2. Differentiate into teratomas or teratocarcinomas when placed in adult histocompatible or immunosuppressed mice 3. In vivo differentiation when introduced into the blastocoels cavity of a preimplantation embryo o
ES and EG cells contribute to every cell type, including the germline
o
EC cells colonies most embryonic lineages, but generally do not
colonies the germline
In vitro methods to grow stem cells Growing embryonic stem cells in the laboratory •
Growing cells in the laboratory is known as cell culture. Human embryonic stem cells are isolated by transferring the inner cell mass into a plastic laboratory culture dish that contains a nutrient broth known as culture medium.
•
The cells divide and spread over the surface of the dish. The inner surface of the culture dish is typically coated with mouse embryonic skin cells that have been treated so they will not divide. This coating layer of cells is called a feeder layer. The reason for having the mouse cells in the bottom of the culture dish is to give the inner cell mass cells a sticky surface to which they can attach. Also, the feeder cells release nutrients into the culture medium. Recently, scientists have begun to devise ways of growing embryonic stem cells without the mouse feeder cells. This is a significant scientific advancement because of the risk that viruses or other macromolecules in the mouse cells may be transmitted to the human cells.
•
Over the course of several days, the cells of the inner cell mass proliferate and begin to crowd the culture dish. When this occurs, they are removed gently and plated into several fresh culture dishes. The process of replating the cells is repeated many times and for many months, and is called subculturing. Each cycle of subculturing the cells is referred to as a passage.
•
After six months or more, the original 30 cells of the inner cell mass yield millions of embryonic stem cells. Embryonic stem cells that have proliferated in cell culture for six or more months without differentiating, are pluripotent, and appear genetically normal are referred to as an embryonic stem cell line.
Once cell lines are established, or even before that stage, batches of them can be frozen and shipped to other laboratories for further culture and experimentation.
Similarities and differences between embryonic, adult and fetal stem cells Adult and embryonic stem cells differ in the number and type of differentiated cells types they can become.
• Embryonic stem cells are the most versatile because they can become any cell in the body including fetal stem cells and adult stem cells (pluripotent). Adult stem cells are more specialized since they are assigned to a specific cell family such as blood cells, nerve cells etc.. These are generally limited to differentiating into different cell types of their tissue of origin •
Large numbers of embryonic stem cells can be relatively easily grown in culture, while adult stem cells are rare in mature tissues and methods for expanding their numbers in cell culture have not yet been worked out. This is an important distinction, as large numbers of cells are needed for stem cell replacement therapies.
•
A potential advantage of using stem cells from an adult is that the patient's own cells could be expanded in culture and then reintroduced into the patient. The use of the patient's own adult stem cells would mean that the cells would not be rejected by the immune system. This represents a significant advantage as immune rejection is a difficult problem that can only be circumvented with immunosuppressive drugs.Embryonic stem cells from a donor introduced into a patient could cause transplant rejection. However, whether the recipient would reject donor embryonic stem cells has not been determined in human experiments.
Advantages, Disadvantages and Ethical Issues of Stem Cells Embryonic Stem Cells Advantages •
Because they have the potential to become any cell in the human body, embryonic stem cells are commonly considered to hold the most promise for treating disease and replacing tissue and cells
•
Large numbers can be easily grown in the laboratory
Disadvantages •
Safety and effectiveness in humans has not yet been determined
•
Because they have the potential to become any cell in the human body, they are difficult for scientists to control
•
They can grow out-of-control forming tumors.
•
They can change into unintended types of cells in the body. For example cells intended to become liver cells may become pancreatic cells
•
The Patient's immune system rejection of embryonic cells has yet to be overcome
Ethical Issues •
Many people oppose embryonic stem cell research because they believe that once formed, the embryo is a human life that should not be destroyed. This is a very significant political, moral, and religious issue for many
Adult Stem Cells Advantages •
Have been safely used in humans for over 30 years
•
No danger of immune system rejection with cells from the patient's own body
•
Extremely low risk of tumor growth
•
Easier to control than embryonic cells
Disadvantages •
Present in the body in very small numbers
•
More limited in what they can become than fetal or embryonic cells
•
More difficult to grow in the laboratory
Ethical Issues •
[1]
No significant ethical issues For simplicity, this fact sheet treats umbilical cord blood stem cells and fetal
stem cells as adult stem cells and embryonic stem cells respectively. [2]
The technical term for this progression is differentiation.
[3]
The technical term for this transformation is plasticity.
[4]
VesCell™ has overcome this obstacle
While "stem cells" have become a commonplace term in the news today, many people only have a vague idea of what stem cells are, where they come from and what they do. Below, we have put together a simple guide on stem cells.
Application Transplantation Research—Restoring Vital Body Functions
Stem cells may hold the key to replacing cells lost in many devastating diseases like Parkinson's disease, diabetes, chronic heart disease, end-stage kidney disease, liver failure, and cancer are just a few for which stem cells have therapeutic potential. Today, science has brought us to a point where the immune response can be subdued, so that organs from one person can be used to replace the diseased organs and tissues of another.
The use of stem cells to generate replacement tissues for treating neurological diseases is a major focus of research. Spinal cord injury, multiple sclerosis, Parkinson's disease, and Alzheimer's disease are among those diseases for which the concept of replacing destroyed or dysfunctional cells in the brain or spinal cord is a practical goal.
Another major discovery frontier for research on adult and embryonic stem cells is the development of transplantable pancreatic tissues that can be used to treat diabetes. Scientists in academic and industrial research are vigorously pursuing all possible avenues of research, including ways to direct the specialization of adult and embryonic stem cells to become pancreatic islet-like cells that produce insulin and can be used to control blood glucose levels. Researchers have recently shown that human embryonic stem cells to be directly differentiated into cells that produce insulin.
Therapeutic Delivery Systems Stem cell-based therapies are a major area of investigation in cancer research. For many years, restoration of blood and immune system function has been used as a component in the care of cancer patients who have been treated with chemotherapeutic agents. Now, researchers are trying to devise more ways to use specialized cells derived from stem cells to target specific cancerous cells and directly deliver treatments that will destroy or modify them.
Cell nuclear transfer Cell nuclear transfer is a technique, which has the potential to create copies of healthy cells to replace or repair damaged or diseased tissues and organs. It involves removing the nucleus from a donated egg and fusing it with a healthy adult cell. The egg-cell combination is then stimulated to develop into a blastocyst, from which embryonic stem cells can be extracted after five days of growth. Obtaining stem cells for potential therapies this way is known as therapeutic cloning.
Cell therapy Cell therapy can be defined as a group of new techniques, or technologies, that rely on replacing diseased or dysfunctional cells with healthy, functioning ones. These new techniques are being applied to a wide range of human diseases, including many types of cancer, neurological diseases such as Parkinson's and Lou Gehrig's Disease, spinal cord injuries, and diabetes. Replacing dead cells in the retina with new ones may someday cure even presently incurable eye diseases such as glaucoma and macular degeneration. To understand how cell therapy works, it helps to understand the role of cells in the body.
Two biological hurdles to stem cell therapy Immune rejection Patients receiving a graft of embryonic stem cells or adult stem cells sourced from cadavers would probably be treated in much the same way that organ transplant recipients are treated. The grafts would be matched to the individual patient and antirejection drugs would be used. Patients receiving brain cells may not need these drugs; the brain seems to get away with less surveillance by the immune system than other parts of the body. And there is one type of stem cell known as a mesenchymal stem cell that seems to evade detection by the immune system. Everyone carries mesenchymal stem cells in their bone marrow; they normally give rise to cartilage, bone or muscle cells. If these cells do not trigger immune rejection they could be used in future treatments of bone and joint diseases or repair heart muscle damaged during a heart attack. If patients provide their own stem cells, then of course immune rejection is no problem. Leukaemia patients routinely rely on their own stem cells. A reserve of their bloodforming stem cells (found in bone marrow, but different from mesenchymal stem cells) is stored away. After cancer therapy, which destroys stem cells, patients rely on the stored stem cells to rapidly restore their red and white blood cell counts to normal.
Burn patients rely on the stem cells present in a tiny square patch of skin to seed the growth of metres of new skin in the culture dish.
Cancer Any stem cell, adult or embryonic, has the ammunition it needs to give rise to cancer: an explosive ability to grow and to change into other types of cells. In fact, researchers now realise that at the heart of many common cancers lies an adult stem cell gone awry. Any stem cell lines injected into patients have to be carefully tested first in animals to see if they give rise to cancer. Though cautious, researchers believe they will be able to tame the tendency of stem cells to form cancers.
Solution to the problem One way to avoid the problem of rejection is to use stem cells that are genetically identical to the host. This is already possible in the rare situations when the patient has healthy stem cells in an undamaged part of the body (like the stem cells being used to replace damaged corneas). But even where no "autologous" stems cells are available, there may be a solution: using somatic-cell nuclear transfer (but with no goal of attempting to implant the resulting blastocyst in a uterus). In this technique, •
A human egg has its own nucleus removed and replaced by
•
a nucleus taken from a somatic (e.g., skin) cell of the patient.
•
The now-diploid egg is allowed to develop in culture to the blastocyst stage when
•
embryonic stem cells can be harvested and grown up in culture.
•
When they have acquired the desired properties, they can be implanted in the patient with no fear of rejection.
While an exciting prospect, there are still problems with the method that must be solved. •
Imprinted Genes. Sperm and eggs each contain certain genes that carry an "imprint" identifying them later in the fertilized egg as being derived from the father or mother respectively. Creating an egg with a nucleus taken from an adult cell may not allow a proper pattern of imprinting to be established. When the diploid adult nucleus is inserted into the enucleated egg (at least those of sheep and mice), the new nucleus becomes "reprogrammed". What reprogramming actually means still must be learned, but perhaps it involves the proper methylation and demethylation of imprinted genes. For example, the inactive X chromosome in adult female cells must be reactivated in the egg, and this actually seems to happen.
•
Aneuploidy. In primates (in contrast to sheep, cattle, and mice), the process of removing the resident nucleus causes molecules associated with the centrosome to be lost as well. Although injecting a donor nucleus allows mitosis to begin, spindle formation may be disrupted, and the resulting cells fail to get the correct complement of chromosomes (aneuploidy).
•
Somatic Mutations. This procedure also raises the spectre of amplifying the effect(s) of somatic mutations. In other words, mutations that might be well-tolerated in a single somatic cell of the adult (used to provide the nucleus) might well turn out to be quite harmful when they become replicated in a clone of cells injected later into the patient.
Possible Solutions to the Ethical Controversy •
ES cells can be derived
from a single cell removed from an 8-cell morula. The success
of
preimplantation
genetic diagnosis (PGD) in humans shows that removing a single cell from the morula does not destroy it — the remaining cells can develop into a blastocyst, implant, and develop into a healthy baby. Furthermore, the single cell removed for PGD can first be allowed to divide with one daughter used for PGD and the •
other
a
potential
source
of
an
ES
cell
line.
In altered nuclear transfer (ANT) — a modified version of SCNT (somatic-cell
nuclear transfer) — a gene necessary for later implantation (Cdx2 — encoding a homeobox transcription factor) is turned off (by RNA interference) in the donor nucleus before the nucleus is inserted into the egg. The blastocyst that develops o
has a defective trophoblast that cannot implant in a uterus;
o
but the cells of the inner cell mass are still capable of developing into cultures of ES cells. (The gene encoding the interfering RNA can then be removed using the Cre/loxP technique.)
•
"Reprogram" adult cells so that they regain the pluripotency of embryonic stem
(ES) cells. Takahashi, K. et al., Cell, 25 August 2006, report that introducing extra copies of only 4 genes into adult mouse fibroblasts enables them to regain most (but not all) of the properties of ES cells (e.g. able to differentiate into ecto, meso, and endodermal cells). The four genes: c-Myc, Sox2, Oct3/4, Klf4. •
Jose Cibelli and his team at Advanced Cell Technology report in the 1 February
2002 issue of Science that they have succeeded in
o
stimulating monkey oocytes to begin dividing without completing meiosis II (therefore still 2n)
o
growing these until the blastocyst stage, from which they were able to harvest
o
If this form of cloning by parthenogenesis works in humans, it would have
o
the advantage that no babies could be produced if the blastocyst should be implanted (two identical genomes cannot produce a viable mammal — probably because of incorrect imprinting);
o
the disadvantage that it will only help females (because only they can provide an oocyte!) (But men may have a procedure that works for them — below.)
•
On 24 March 2006, Nature published an online report that a group of German
scientists had been able to derive pluripotent stem cells from the stem cells that make spermatogonia in the mouse. Both in vitro and when injected into mouse blastocysts, these cells differentiated in a variety of ways including representatives of all three germ layers. If this could work in humans, it would o
provide a source of stem cells whose descendants would be "patientspecific"; that is, could be transplanted back into the donor (men only!) without fear of immune rejection.
o
avoid the controversy surrounding the need to destroy human blastocysts to provide embryonic stem cells.
•
The 7 January 2007 issue of Nature Biotechnology reports the successful
production of amniotic fluid-derived stem cells ("AFS"). These are present in the amniotic fluid removed during amniocentesis. With the proper culture conditions, they have been shown to be able to differentiate into a variety of cell types including o
ectoderm (neural tissue)
o
mesoderm (e.g., bone, muscle) and
o
endoderm (e.g., liver).
Conclusions Two important points about embryonic and adult stem cells have emerged so far: the cells are different and present immense research opportunities for potential therapy. As research goes forward, scientists will undoubtedly find other similarities and differences between adult and embryonic stem cells. During the next several years, it will be important to compare embryonic stem cells and adult stem cells in terms of their ability to proliferate, differentiate, survive and function after transplant, and avoid immune rejection. Investigators have shown that differentiated cells generated from both adult and embryonic stem cells can repair or replace damaged cells and tissues in animal studies. Scientists upon making new discoveries often verify reported results in different laboratories and under different conditions. Similarly, they will often conduct experiments with different animal models or, in this case, different cell lines. However, there have been very few studies that compare various stem cell lines with each other. It may be that one source proves better for certain applications, and a different cell source proves better for others. For researchers and patients, there are many practical questions about stem cells that cannot yet be answered. How long will it take to develop therapies for Parkinson's Disease and diabetes with and without human pluripotent stem cells? Can the full range of new therapeutic approaches be developed using only adult stem cells? How many different sources of stem cells will be needed to generate the best treatments in the shortest period of time? Predicting the future of stem cell applications is impossible, particularly given the very early stage of the science of stem cell biology. To date, it is impossible to predict which stem cells—those derived from the embryo, the fetus, or the adult—or which methods for manipulating the cells, will best meet the needs of basic research and clinical applications. The answers clearly lie in conducting more research.
Key Achievements in Stem Cell Research 1957 Successful first attempt at intravenous infusion of bone marrow in patients receiving radiation and chemotherapy, Mary Imogene Bassett Hospital, Cooperstown, USA. 1959 Researchers at Jackson Laboratory, Maine, USA, identify a strain of mouse in which testicular teratomas occur with an appreciable frequency. 1963 The first quantitative descriptions of the self-renewing activities of transplanted mouse bone marrow cells, at University of Toronto, Canada. 1974 Researchers at the University of Pennsylvania, USA, demonstrate that mouse EC cells can participate in the development of organisms as well as teratomas. 1978 First IVF baby born, following fertilisation of human eggs outside the body by scientists at Cambridge University, UK. 1981 Successful cultivation of mouse embryonic stem (ES) cells from explanted inner cell mass cells, at the University of California, USA, and Cambridge University, UK. 1987 Development of the technology needed for mutagenesis by gene targeting in mice using ES cells, at University of Utah and University of Cincinatti, USA. 1992 Development of methods for culturing embryonic germ (EG) cells developed at Vanderbilt University and National Cancer Institute, USA. 1996 A sheep is cloned through cell nuclear replacement techniques at the Roslin Institute, Edinburgh University, Scotland. 1996 Primate ES cell lines derived at the Wisconsin Primate Research Center, USA. 1998 First human ES cell lines are derived from human blastocysts at the Wisconsin Primate Research Center. 1998 Researchers at the John Hopkins University, USA, culture human EG cells taken from fetal tissue.
1999 Researchers at the Cedars-Sinai Medical Center in Los Angeles, USA, remove 10 – 15 neural stem cells from a Parkinson’s disease patient and used them to reproduce 6 million dopaminergic neural stem cells. These were reintroduced into the patient’s brain tissue, producing a 62% increase in dopamine uptake and a 40–50% improvement in certain motor tasks. 1999 Researchers at the Baylor College of Medicine, USA, turn adult somatic stem cells derived from skeletal muscle into blood cells. 1999 Canadian researchers generate a variety of blood cell types, including myeloid, lymphoid and early hematopoietic, from adult somatic neural stem cells. 2002 Research at the University of Minnesota Medical School shows that adult somatic stem cells, previously thought to have very limited potential for specialisation, can differentiate into unrelated cell types, such as nerve and blood cells in some circumstances. 2003 Researchers at King’s College London generate the UK’s first human ES cell line. 2003 The International Stem Cell Forum (ISCF) is established to encourage international collaboration and funding support for stem cell research. 2004 The ISCF begins a review of ethics and regulation relating to stem cell research across the globe. 2006 On behalf of the ISCF, the Australian National Health and Medical Research Council begins a review of intellectual property rights related to stem cell research across the world, which will be key in encouraging further research and development worldwide. 2006 Led by the UK Medical Research Council, the International Stem Cell Forum (ISCF) sponsors an international project coordinated by Sheffield University to characterise 59 human embryonic stem cell lines.
A stem cell is a special kind of cell that has a unique capacity to renew itself and to give rise to specialized cell types. Although most cells of the body, such as heart cells or skin cells, are committed to conduct a specific function, a stem cell is uncommitted and remains uncommitted, until it receives a signal to develop into a specialized cells
•
In 1998, for the first time, investigators were able to isolate this class of pluripotent stem cell from early human embryos and grow them in culture.At about the same time as scientists were beginning to explore human pluripotent stem cells from embryos and fetal tissue, a flurry of new information was emerging about a class of stem cells that have been in clinical use for years—so-called adult stem cells. An adult stem cell is an undifferentiated cell that is found in a differentiated (specialized) tissue in the adult, such as blood. It can yield the specialized cell types of the tissue from which it originated. In the body, it too, can renew itself
•
The one-cell embryo develops into a fully formed human being through a process called cell differentiation. As an embryo develops, embryonic stem cells form the different cells that make up our bodies. As they go further along the developmental pathway, they become more and more specialised until they are only able to perform one function..
•
To be able to harness the therapeutic potential of stem cells, scientists need to learn how to direct them to differentiate appropriately, for example, to generate muscle cells for damaged hearts or neurones for damaged brains. Another challenge is to ensure they do not continue to multiply in an uncontrolled way and not form a tumour.
•
Current science indicates that, although both of these cell types hold enormous promise, adult and embryonic stem cells differ in important ways. What is not known is the extent to which these different cell types will be useful for the development of cell-based therapies to treat disease.
What Are Stem Cells? Stem cells are found in a number of areas of the body and occur at the earliest stages of human development through to adulthood. Whether they come from an early embryo, a fetus or an adult, stem cells have two key properties. : Firstly, they have the ability to reproduce themselves almost indefinitely through cell division. (Self renewal). Secondly, Regulated by intrinsic signals and the external microenvironment .they can be directed to generate cells with special functions that make up the tissues and organs of the body, such as the beating cells of the heart or the insulin-producing cells of the pancreas (unlimited potency). This capacity to both proliferate and form different types of cells makes them ideal for replacing tissue that is lost. They are 'all-purpose' cells.
Classification of Stem cells Stem cells are classified on the basis of 1. The extent to which they can differentiate into different cell types, 2. Source of stem cells.
Extent to which they can differentiate into different cell types: Stem cells are cells that divide by mitosis to form two stem cells, thus increasing the size of the stem cell "pool", - One daughter that goes on to differentiate, and - Another daughter that retains its stem-cell properties.
Pluripotent, embryonic stem cells originate as inner mass cells with in a blastocyst. The stem cells can become any tissue in the body, excluding a placenta. Only the morula's cells are totipotent, able to become all tissues and a placenta.
1. Totipotent cells. In mammals, totipotent cells have the potential to become o
Any type in the adult body;
o
Any cell of the extra-embryonic membranes (i.e., placenta).
The only totipotent cells are the fertilized egg and the first 4 or so cells produced by its cleavage (as shown by the ability of mammals to produce identical twins, triplets, etc.). 2. Pluripotent stem cells. These are true stem cells, with the potential to make any differentiated cell in the body (but probably not all those of the extra-embryonic membranes, which are derived from the trophoblast).
Three types of pluripotent stem cells have been found o
Embryonic Stem (ES) Cells. These can be isolated from the inner cell mass (ICM)
of the blastocyst — the stage of embryonic development when implantation occurs. For humans, excess embryos produced during in vitro fertilization (IVF) procedures are used. Harvesting ES cells from human blastocysts is controversial because it destroys the embryo, which could have been implanted to produce another baby (but often was simply going to be discarded). o
Embryonic Germ (EG) Cells. These can be isolated from the precursor to the
gonads in aborted fetuses. . o
Embryonic Carcinoma (EC) Cells. These can be isolated from teratocarcinomas, a
tumor that occasionally occurs in a gonad of a fetus. Unlike the other two, they are usually aneuploid. All three of these types of pluripotent stem cells - can only be isolated from embryonic or fetal tissue; - can be grown in culture, but only with special methods to prevent them from differentiating.
3. Multipotent stem cells These are true stem cells but can only differentiate into a limited number of types. For example, the bone marrow contains multipotent stem cells that give rise to all the cells of the blood but not to other types of cells. Multipotent stem cells are found in adult animals; perhaps most organs in the body (e.g., brain, liver) contain them where they can replace dead or damaged cells. These adult stem cells may also be the cells that — when one accumulates sufficient mutations — produce a clone of cancer cells.
On the basis of source: 1. Embryonic stem cells 2. Embryonic germ cells 3. Adult stem cells
1. Embryonic stem cells (ESCs) are derived from 4- to 5-day-old embryos. At this stage, the embryos are spherical and are known as blastocysts. Each blastocyst consists of 50 to 150 cells and includes three structures: an outer layer of cells, a fluid-filled cavity, and a group of about 30 pluripotent cells at one end of the cavity, called the inner cell mass.
Properties of an Embryonic Stem Cell Derived from the inner cell mass/epiblast of the blastocyst. Can be induced to continue proliferating or to differentiate. Clonogenic i.e. a single ES cell can give rise to a colony of genetically identical cells, or clones, which have the same properties as the original cell. Exhibit and maintain a stable, full (diploid), normal complement of chromosomes (karyotype). Pluripotent ES cells can give rise to differentiated cell types that are derived from all three primary germ layers of the embryo (endoderm, mesoderm, and ectoderm).
2. Embryonic (or fetal) germ cells Embryonic germ cells are pluripotent stem cells derived from so-called primordial germ cells, which are the cells that give rise to the gametes (sperm and eggs) in adults. Scientists obtain primordial germ cells from the area in a 5- to 9-week-old embryo/fetus destined to become either the testicles or the ovaries (the dividing line between embryo and fetus is the end of the 8th week).
Like ESCs, the primordial germ cells are transferred into a specially treated plastic culture dish, where they form germ cell colonies.
Less research has been performed using embryonic germ (EG) cells than ESCs, mostly because the embryos used for deriving EG cells are deliberately aborted, while the blastocysts used for deriving ESCs are produced through in vitro fertilization in a fertility clinic. EG cells are also difficult to maintain in cell culture because they have a tendency to differentiate spontaneously.
Factors required for maintaining Pluripotency •
Leukaemia inhibitory factor ( LIF )
•
Neuropoeitic and haematopoietic cytokine
•
Interleukin 6 family of cytokine receptors
•
Receptors associated with tyrosine kinase - JAK
•
Activate the STAT family of transcription factors
•
Signal Transducer and Activator of Transcription
3. Adult stem cells These cells share at least two characteristics. •
First, they can make identical copies of themselves for long periods of time; this ability to proliferate is referred to as long-term self-renewal.
•
Second, they can give rise to mature cell types that have characteristic morphologies (shapes) and specialized functions.
However, they are also found in children and can be extracted from umbilical cord blood.
The primary roles of adult stem cells in the body are to maintain and repair the tissues in which they are found. They are usually thought of as multipotent cells, giving rise to a closely related family of cells within the tissue.
A potential advantage of using adult stem cells from a patient is that the patient’s own cells could be expanded in culture, treated to differentiate into the desired cells, and then reintroduced into the patient.
The use of the patient’s own cells would eliminate any possibility that they might be rejected by the immune system.
Disadvantages of using adult stem cells are that they are rare in mature tissues and it is more difficult to expand their numbers in cell culture, compared with ESCs.
Differentiation
Adult stem cell differentiation
Figure 2. Hematopoietic and stromal stem cell differentiation. Click here for larger image. As indicated above, scientists have reported that adult stem cells occur in many tissues and that they enter normal differentiation pathways to form the specialized cell types of the tissue in which they reside. Adult stem cells may also exhibit the ability to form specialized cell types of other tissues, which is known as transdifferentiation or plasticity.The following are examples of differentiation pathways of adult stem cells (Figure 2). Hematopoietic stem cells give rise to all the types of blood cells: red blood cells, B lymphocytes, T lymphocytes, natural killer cells, neutrophils, basophils, eosinophils, monocytes, macrophages, and platelets.
Bone marrow stromal cells (mesenchymal stem cells) give rise to a variety of cell types: bone cells (osteocytes), cartilage cells (chondrocytes), fat cells (adipocytes), and other kinds of connective tissue cells such as those in tendons. neural stem cells in the brain give rise to its three major cell types: nerve cells (neurons) and two categories of non-neuronal cells—astrocytes and oligodendrocytes. Epithelial stem cells in the lining of the digestive tract occur in deep crypts and give rise to several cell types: absorptive cells, goblet cells, Paneth cells, and enteroendocrine cells. Skin stem cells occur in the basal layer of the epidermis and at the base of hair follicles. The epidermal stem cells give rise to keratinocytes, which migrate to the surface of the skin and form a protective layer. The follicular stem cells can give rise to both the hair follicle and to the epidermis. Hematopoietic stem cells may differentiate into: three major types of brain cells (neurons, oligodendrocytes, and astrocytes); skeletal muscle cells; cardiac muscle cells; and liver cells. Bone marrow stromal cells may differentiate into: cardiac muscle cells and skeletal muscle cells. Brain stem cells may differentiate into: blood cells and skeletal muscle cells.
Markers used to distinguish between pluripotent stem cells and their differentiated derivatives •
•
Cell-surface markers recognized by monoclonal antibodies o
Stage-specific embryonic antigens
o
Tumour-recognition antigens
Oct 4 o
POU-domain transcription factor
o
Differentiation associated with down-regulation of Oct4 levels
o
Downregulation of the Oct4 gene results in differentiation and loss of
pluripotent cells
Figure E.i.1. Identifying Cell Surface Markers Using Fluorescent Tags
Pluripotency tested in three independent assays 1. Able to differentiate in vitro in a Petri dish 2. Differentiate into teratomas or teratocarcinomas when placed in adult histocompatible or immunosuppressed mice 3. In vivo differentiation when introduced into the blastocoels cavity of a preimplantation embryo o
ES and EG cells contribute to every cell type, including the germline
o
EC cells colonies most embryonic lineages, but generally do not
colonies the germline
In vitro methods to grow stem cells Growing embryonic stem cells in the laboratory •
Growing cells in the laboratory is known as cell culture. Human embryonic stem cells are isolated by transferring the inner cell mass into a plastic laboratory culture dish that contains a nutrient broth known as culture medium.
•
The cells divide and spread over the surface of the dish. The inner surface of the culture dish is typically coated with mouse embryonic skin cells that have been treated so they will not divide. This coating layer of cells is called a feeder layer. The reason for having the mouse cells in the bottom of the culture dish is to give the inner cell mass cells a sticky surface to which they can attach. Also, the feeder cells release nutrients into the culture medium. Recently, scientists have begun to devise ways of growing embryonic stem cells without the mouse feeder cells. This is a significant scientific advancement because of the risk that viruses or other macromolecules in the mouse cells may be transmitted to the human cells.
•
Over the course of several days, the cells of the inner cell mass proliferate and begin to crowd the culture dish. When this occurs, they are removed gently and plated into several fresh culture dishes. The process of replating the cells is repeated many times and for many months, and is called subculturing. Each cycle of subculturing the cells is referred to as a passage.
•
After six months or more, the original 30 cells of the inner cell mass yield millions of embryonic stem cells. Embryonic stem cells that have proliferated in cell culture for six or more months without differentiating, are pluripotent, and appear genetically normal are referred to as an embryonic stem cell line.
Once cell lines are established, or even before that stage, batches of them can be frozen and shipped to other laboratories for further culture and experimentation.
Similarities and differences between embryonic, adult and fetal stem cells Adult and embryonic stem cells differ in the number and type of differentiated cells types they can become.
• Embryonic stem cells are the most versatile because they can become any cell in the body including fetal stem cells and adult stem cells (pluripotent). Adult stem cells are more specialized since they are assigned to a specific cell family such as blood cells, nerve cells etc.. These are generally limited to differentiating into different cell types of their tissue of origin •
Large numbers of embryonic stem cells can be relatively easily grown in culture, while adult stem cells are rare in mature tissues and methods for expanding their numbers in cell culture have not yet been worked out. This is an important distinction, as large numbers of cells are needed for stem cell replacement therapies.
•
A potential advantage of using stem cells from an adult is that the patient's own cells could be expanded in culture and then reintroduced into the patient. The use of the patient's own adult stem cells would mean that the cells would not be rejected by the immune system. This represents a significant advantage as immune rejection is a difficult problem that can only be circumvented with immunosuppressive drugs.Embryonic stem cells from a donor introduced into a patient could cause transplant rejection. However, whether the recipient would reject donor embryonic stem cells has not been determined in human experiments.
Advantages, Disadvantages and Ethical Issues of Stem Cells Embryonic Stem Cells Advantages •
Because they have the potential to become any cell in the human body, embryonic stem cells are commonly considered to hold the most promise for treating disease and replacing tissue and cells
•
Large numbers can be easily grown in the laboratory
Disadvantages •
Safety and effectiveness in humans has not yet been determined
•
Because they have the potential to become any cell in the human body, they are difficult for scientists to control
•
They can grow out-of-control forming tumors.
•
They can change into unintended types of cells in the body. For example cells intended to become liver cells may become pancreatic cells
•
The Patient's immune system rejection of embryonic cells has yet to be overcome
Ethical Issues •
Many people oppose embryonic stem cell research because they believe that once formed, the embryo is a human life that should not be destroyed. This is a very significant political, moral, and religious issue for many
Adult Stem Cells Advantages •
Have been safely used in humans for over 30 years
•
No danger of immune system rejection with cells from the patient's own body
•
Extremely low risk of tumor growth
•
Easier to control than embryonic cells
Disadvantages •
Present in the body in very small numbers
•
More limited in what they can become than fetal or embryonic cells
•
More difficult to grow in the laboratory
Ethical Issues •
[1]
No significant ethical issues For simplicity, this fact sheet treats umbilical cord blood stem cells and fetal
stem cells as adult stem cells and embryonic stem cells respectively. [2]
The technical term for this progression is differentiation.
[3]
The technical term for this transformation is plasticity.
[4]
VesCell™ has overcome this obstacle
While "stem cells" have become a commonplace term in the news today, many people only have a vague idea of what stem cells are, where they come from and what they do. Below, we have put together a simple guide on stem cells.
Application Transplantation Research—Restoring Vital Body Functions
Stem cells may hold the key to replacing cells lost in many devastating diseases like Parkinson's disease, diabetes, chronic heart disease, end-stage kidney disease, liver failure, and cancer are just a few for which stem cells have therapeutic potential. Today, science has brought us to a point where the immune response can be subdued, so that organs from one person can be used to replace the diseased organs and tissues of another.
The use of stem cells to generate replacement tissues for treating neurological diseases is a major focus of research. Spinal cord injury, multiple sclerosis, Parkinson's disease, and Alzheimer's disease are among those diseases for which the concept of replacing destroyed or dysfunctional cells in the brain or spinal cord is a practical goal.
Another major discovery frontier for research on adult and embryonic stem cells is the development of transplantable pancreatic tissues that can be used to treat diabetes. Scientists in academic and industrial research are vigorously pursuing all possible avenues of research, including ways to direct the specialization of adult and embryonic stem cells to become pancreatic islet-like cells that produce insulin and can be used to control blood glucose levels. Researchers have recently shown that human embryonic stem cells to be directly differentiated into cells that produce insulin.
Therapeutic Delivery Systems Stem cell-based therapies are a major area of investigation in cancer research. For many years, restoration of blood and immune system function has been used as a component in the care of cancer patients who have been treated with chemotherapeutic agents. Now, researchers are trying to devise more ways to use specialized cells derived from stem cells to target specific cancerous cells and directly deliver treatments that will destroy or modify them.
Cell nuclear transfer Cell nuclear transfer is a technique, which has the potential to create copies of healthy cells to replace or repair damaged or diseased tissues and organs. It involves removing the nucleus from a donated egg and fusing it with a healthy adult cell. The egg-cell combination is then stimulated to develop into a blastocyst, from which embryonic stem cells can be extracted after five days of growth. Obtaining stem cells for potential therapies this way is known as therapeutic cloning.
Cell therapy Cell therapy can be defined as a group of new techniques, or technologies, that rely on replacing diseased or dysfunctional cells with healthy, functioning ones. These new techniques are being applied to a wide range of human diseases, including many types of cancer, neurological diseases such as Parkinson's and Lou Gehrig's Disease, spinal cord injuries, and diabetes. Replacing dead cells in the retina with new ones may someday cure even presently incurable eye diseases such as glaucoma and macular degeneration. To understand how cell therapy works, it helps to understand the role of cells in the body.
Two biological hurdles to stem cell therapy Immune rejection Patients receiving a graft of embryonic stem cells or adult stem cells sourced from cadavers would probably be treated in much the same way that organ transplant recipients are treated. The grafts would be matched to the individual patient and antirejection drugs would be used. Patients receiving brain cells may not need these drugs; the brain seems to get away with less surveillance by the immune system than other parts of the body. And there is one type of stem cell known as a mesenchymal stem cell that seems to evade detection by the immune system. Everyone carries mesenchymal stem cells in their bone marrow; they normally give rise to cartilage, bone or muscle cells. If these cells do not trigger immune rejection they could be used in future treatments of bone and joint diseases or repair heart muscle damaged during a heart attack. If patients provide their own stem cells, then of course immune rejection is no problem. Leukaemia patients routinely rely on their own stem cells. A reserve of their bloodforming stem cells (found in bone marrow, but different from mesenchymal stem cells) is stored away. After cancer therapy, which destroys stem cells, patients rely on the stored stem cells to rapidly restore their red and white blood cell counts to normal.
Burn patients rely on the stem cells present in a tiny square patch of skin to seed the growth of metres of new skin in the culture dish.
Cancer Any stem cell, adult or embryonic, has the ammunition it needs to give rise to cancer: an explosive ability to grow and to change into other types of cells. In fact, researchers now realise that at the heart of many common cancers lies an adult stem cell gone awry. Any stem cell lines injected into patients have to be carefully tested first in animals to see if they give rise to cancer. Though cautious, researchers believe they will be able to tame the tendency of stem cells to form cancers.
Solution to the problem One way to avoid the problem of rejection is to use stem cells that are genetically identical to the host. This is already possible in the rare situations when the patient has healthy stem cells in an undamaged part of the body (like the stem cells being used to replace damaged corneas). But even where no "autologous" stems cells are available, there may be a solution: using somatic-cell nuclear transfer (but with no goal of attempting to implant the resulting blastocyst in a uterus). In this technique, •
A human egg has its own nucleus removed and replaced by
•
a nucleus taken from a somatic (e.g., skin) cell of the patient.
•
The now-diploid egg is allowed to develop in culture to the blastocyst stage when
•
embryonic stem cells can be harvested and grown up in culture.
•
When they have acquired the desired properties, they can be implanted in the patient with no fear of rejection.
While an exciting prospect, there are still problems with the method that must be solved. •
Imprinted Genes. Sperm and eggs each contain certain genes that carry an "imprint" identifying them later in the fertilized egg as being derived from the father or mother respectively. Creating an egg with a nucleus taken from an adult cell may not allow a proper pattern of imprinting to be established. When the diploid adult nucleus is inserted into the enucleated egg (at least those of sheep and mice), the new nucleus becomes "reprogrammed". What reprogramming actually means still must be learned, but perhaps it involves the proper methylation and demethylation of imprinted genes. For example, the inactive X chromosome in adult female cells must be reactivated in the egg, and this actually seems to happen.
•
Aneuploidy. In primates (in contrast to sheep, cattle, and mice), the process of removing the resident nucleus causes molecules associated with the centrosome to be lost as well. Although injecting a donor nucleus allows mitosis to begin, spindle formation may be disrupted, and the resulting cells fail to get the correct complement of chromosomes (aneuploidy).
•
Somatic Mutations. This procedure also raises the spectre of amplifying the effect(s) of somatic mutations. In other words, mutations that might be well-tolerated in a single somatic cell of the adult (used to provide the nucleus) might well turn out to be quite harmful when they become replicated in a clone of cells injected later into the patient.
Possible Solutions to the Ethical Controversy •
ES cells can be derived
from a single cell removed from an 8-cell morula. The success
of
preimplantation
genetic diagnosis (PGD) in humans shows that removing a single cell from the morula does not destroy it — the remaining cells can develop into a blastocyst, implant, and develop into a healthy baby. Furthermore, the single cell removed for PGD can first be allowed to divide with one daughter used for PGD and the •
other
a
potential
source
of
an
ES
cell
line.
In altered nuclear transfer (ANT) — a modified version of SCNT (somatic-cell
nuclear transfer) — a gene necessary for later implantation (Cdx2 — encoding a homeobox transcription factor) is turned off (by RNA interference) in the donor nucleus before the nucleus is inserted into the egg. The blastocyst that develops o
has a defective trophoblast that cannot implant in a uterus;
o
but the cells of the inner cell mass are still capable of developing into cultures of ES cells. (The gene encoding the interfering RNA can then be removed using the Cre/loxP technique.)
•
"Reprogram" adult cells so that they regain the pluripotency of embryonic stem
(ES) cells. Takahashi, K. et al., Cell, 25 August 2006, report that introducing extra copies of only 4 genes into adult mouse fibroblasts enables them to regain most (but not all) of the properties of ES cells (e.g. able to differentiate into ecto, meso, and endodermal cells). The four genes: c-Myc, Sox2, Oct3/4, Klf4. •
Jose Cibelli and his team at Advanced Cell Technology report in the 1 February
2002 issue of Science that they have succeeded in
o
stimulating monkey oocytes to begin dividing without completing meiosis II (therefore still 2n)
o
growing these until the blastocyst stage, from which they were able to harvest
o
If this form of cloning by parthenogenesis works in humans, it would have
o
the advantage that no babies could be produced if the blastocyst should be implanted (two identical genomes cannot produce a viable mammal — probably because of incorrect imprinting);
o
the disadvantage that it will only help females (because only they can provide an oocyte!) (But men may have a procedure that works for them — below.)
•
On 24 March 2006, Nature published an online report that a group of German
scientists had been able to derive pluripotent stem cells from the stem cells that make spermatogonia in the mouse. Both in vitro and when injected into mouse blastocysts, these cells differentiated in a variety of ways including representatives of all three germ layers. If this could work in humans, it would o
provide a source of stem cells whose descendants would be "patientspecific"; that is, could be transplanted back into the donor (men only!) without fear of immune rejection.
o
avoid the controversy surrounding the need to destroy human blastocysts to provide embryonic stem cells.
•
The 7 January 2007 issue of Nature Biotechnology reports the successful
production of amniotic fluid-derived stem cells ("AFS"). These are present in the amniotic fluid removed during amniocentesis. With the proper culture conditions, they have been shown to be able to differentiate into a variety of cell types including o
ectoderm (neural tissue)
o
mesoderm (e.g., bone, muscle) and
o
endoderm (e.g., liver).
Conclusions Two important points about embryonic and adult stem cells have emerged so far: the cells are different and present immense research opportunities for potential therapy. As research goes forward, scientists will undoubtedly find other similarities and differences between adult and embryonic stem cells. During the next several years, it will be important to compare embryonic stem cells and adult stem cells in terms of their ability to proliferate, differentiate, survive and function after transplant, and avoid immune rejection. Investigators have shown that differentiated cells generated from both adult and embryonic stem cells can repair or replace damaged cells and tissues in animal studies. Scientists upon making new discoveries often verify reported results in different laboratories and under different conditions. Similarly, they will often conduct experiments with different animal models or, in this case, different cell lines. However, there have been very few studies that compare various stem cell lines with each other. It may be that one source proves better for certain applications, and a different cell source proves better for others. For researchers and patients, there are many practical questions about stem cells that cannot yet be answered. How long will it take to develop therapies for Parkinson's Disease and diabetes with and without human pluripotent stem cells? Can the full range of new therapeutic approaches be developed using only adult stem cells? How many different sources of stem cells will be needed to generate the best treatments in the shortest period of time? Predicting the future of stem cell applications is impossible, particularly given the very early stage of the science of stem cell biology. To date, it is impossible to predict which stem cells—those derived from the embryo, the fetus, or the adult—or which methods for manipulating the cells, will best meet the needs of basic research and clinical applications. The answers clearly lie in conducting more research.
Key Achievements in Stem Cell Research 1957 Successful first attempt at intravenous infusion of bone marrow in patients receiving radiation and chemotherapy, Mary Imogene Bassett Hospital, Cooperstown, USA. 1959 Researchers at Jackson Laboratory, Maine, USA, identify a strain of mouse in which testicular teratomas occur with an appreciable frequency. 1963 The first quantitative descriptions of the self-renewing activities of transplanted mouse bone marrow cells, at University of Toronto, Canada. 1974 Researchers at the University of Pennsylvania, USA, demonstrate that mouse EC cells can participate in the development of organisms as well as teratomas. 1978 First IVF baby born, following fertilisation of human eggs outside the body by scientists at Cambridge University, UK. 1981 Successful cultivation of mouse embryonic stem (ES) cells from explanted inner cell mass cells, at the University of California, USA, and Cambridge University, UK. 1987 Development of the technology needed for mutagenesis by gene targeting in mice using ES cells, at University of Utah and University of Cincinatti, USA. 1992 Development of methods for culturing embryonic germ (EG) cells developed at Vanderbilt University and National Cancer Institute, USA. 1996 A sheep is cloned through cell nuclear replacement techniques at the Roslin Institute, Edinburgh University, Scotland. 1996 Primate ES cell lines derived at the Wisconsin Primate Research Center, USA. 1998 First human ES cell lines are derived from human blastocysts at the Wisconsin Primate Research Center. 1998 Researchers at the John Hopkins University, USA, culture human EG cells taken from fetal tissue.
1999 Researchers at the Cedars-Sinai Medical Center in Los Angeles, USA, remove 10 – 15 neural stem cells from a Parkinson’s disease patient and used them to reproduce 6 million dopaminergic neural stem cells. These were reintroduced into the patient’s brain tissue, producing a 62% increase in dopamine uptake and a 40–50% improvement in certain motor tasks. 1999 Researchers at the Baylor College of Medicine, USA, turn adult somatic stem cells derived from skeletal muscle into blood cells. 1999 Canadian researchers generate a variety of blood cell types, including myeloid, lymphoid and early hematopoietic, from adult somatic neural stem cells. 2002 Research at the University of Minnesota Medical School shows that adult somatic stem cells, previously thought to have very limited potential for specialisation, can differentiate into unrelated cell types, such as nerve and blood cells in some circumstances. 2003 Researchers at King’s College London generate the UK’s first human ES cell line. 2003 The International Stem Cell Forum (ISCF) is established to encourage international collaboration and funding support for stem cell research. 2004 The ISCF begins a review of ethics and regulation relating to stem cell research across the globe. 2006 On behalf of the ISCF, the Australian National Health and Medical Research Council begins a review of intellectual property rights related to stem cell research across the world, which will be key in encouraging further research and development worldwide. 2006 Led by the UK Medical Research Council, the International Stem Cell Forum (ISCF) sponsors an international project coordinated by Sheffield University to characterise 59 human embryonic stem cell lines.
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