Basics of Stem Cell Research: Stem cells are cells found in most,
if not all, multi-cellular organisms. They are characterized by
the ability to renew themselves through mitotic cell division and
differentiating into a diverse range of specialized cell types.
Research in the stem cell field grew out of findings by Canadian
scientists Ernest A. McCulloch and James E. Till in the 1960s.
two broad types of mammalian stem cells are: 1- embryonic stem cells
that are isolated from the inner cell mass of blastocysts; and 2-
adult stem cells that are found in adult tissues. In a developing
embryo, stem cells can differentiate into all of the specialized
embryonic tissues. In adult organisms, stem cells and progenitor
cells act as a repair system for the body, replenishing specialized
cells, but also maintain the normal turnover of regenerative organs,
such as blood, skin or intestinal tissues.
cells can now be grown and transformed into specialized cells with
characteristics consistent with cells of various tissues such as
muscles or nerves through cell culture. Highly plastic adult stem
cells from a variety of sources, including umbilical cord blood
and bone marrow, are routinely used in medical therapies. Embryonic
stem cell research has been plagued by moral and legal problems.
In addition, early transplantation work with embryonic cells indicates
that the transplanted cells create tumors, a critical setback for
long-term work. Thus far, the approximate 70 therapies that use
adult stem cells successfully use stem cells derived from the bone
marrow. This process, called bone marrow apheresis, requires drilling
holes in the hip bone and extracting about one quart of bone marrow
and blood and separating the stem cells from it. This is costly
(over $100,000), painful, and about 5% of the people die from infection
and related problems. It is the last thing you would prefer to do
after a heart attack, but since it works, it is being used. Now,
everyone's goal is to avoid such a difficult treatment by take circulating
blood that can be easily removed (called peripheral blood) and use
that to regenerate needed tissue. However, circulating blood is
not rich enough in stem cells to regenerate tissue; it would take
too much blood to be provide a therapeutic amount of cells.
the goal is to take blood from the arm, as simple as one would give
a blood sample, and use that blood to grow (referred to as "expand")
the cells to a therapeutic amount of cells. It's not easy to do,
and the researchers that are able to do so may change the course
of medical treatment as we know it.
cell research is an exciting and complicated area of science. In
order to better understand what Regenetech is studying in its laboratories,
we invite you to learn more about stem cells, specifically adult
stem cell research, and its exciting impact upon healthcare.
Given the enormous
promise of stem cells to the development of new therapies for the
most devastating diseases, it is important to simultaneously pursue
all lines of research. Science and scientists need to search for
the very best sources of these cells. When they are identified,
regardless of their sources, researchers will use them to pursue
the development of new cell therapies. The development of stem cell
lines, both pluripotent and multipotent, that may produce many tissues
of the human body is an important scientific breakthrough. It is
not too unrealistic to say that this research has the potential
to revolutionize the practice of medicine and improve the quality
and length of life.
This primer explains what stem cells are. Here you can learn more
about what adult stem cells and pluripotent stem cell are, how they
are important to advancing healthcare.
Adult stem cells: Stem cells in an individual after birth.
of bone marrow: Inserting a needle into bone and extracting
bone marrow. A painful and sometimes dangerous procedure. Apheresis
as a term includes extracting peripheral blood.
In blood transfusion and transplantation, a situation in which the
donor and recipient are the same person. Patients scheduled for
non-emergency surgery may be autologous donors by donating blood
for themselves that will be stored until the surgery. An autologous
graft is providing a graft, for example of skin, to yourself.
A cylindrical chamber that is rotated on its axis in a manner
to grow biological cells, which includes cell growth media.
poly-N-acetyllactosamine. An anti-body. CD15 recognizes a human
myelomonocytic antigen. The structure recognized by CD15 antibodies
is lacto-N-fucopentose III. The CD15 antigen is present on greater
than 95% of mature peripheral blood eosinophils and neutrophils
and is present at low density on circulating monocytes. In lymphoid
tissue, CD15 reacts with Reed-Sternberg cells of Hodgkin�s disease
and with granulocytes; however, CD15 reacts with few tissue macrophages
and does not react with dendritic cells.
Sialoadhesin; sialic acid-dependent cytoadhesion molecule. CD33
antigen, detected by WM53 monoclonal antibodies, is expressed on
human peripheral blood monocytes and weakly on granulocytes. Expression
is also found on myeloid progenitor cells, such as granulocyte and
macrophage precursor cells in bone marrow. No reactivity has been
found with normal lymphocytes, erythrocytes and platelets, nor with
pluripotent stem cells.
A surface antigen or protein residing on the surface of a blood
cell. CD34+ protein is present on the surface of hematopoietic stem
and progenitor cells all stages of development. The CD34+ cells
are the only cell type in an apheresis or bone marrow collection
that are usually responsible for blood cell recovery after transplant.
Since it is present on the surface of hematopoietic stem and progenitor
cells, it can be used to test for them.
A cytoplasmic protein used much like CD34+ for determining expansion
of hematopoietic stem and progenitor cells.
A hematopoietic cell useful like CD34+ and CD38- to test expansion
of stem cells.
geometry: The geometry of cells in the human blood. Includes
the spacing, distance between, and physical relationship of the
cells relative to one another.
support: The support one cell provides for an adjacent cell
in the liquid blood.
(CFU-GEMM): The proliferative state of human pluripotent hemopoietic
units granulocyte-macrophage (CFU-GM): A haematopoietic progenitor
cell in the granulocytic series that can grow into a myeloblast
in the presence of appropriate stimulators in vitro. Called also
colony forming u.-culture.
cells: Blood cells drained from an umbilical cord or placenta
immediately after birth. Rich in unexpanded stem cells. Available
only a few hours after birth.
A small protein released by cells that has a specific effect on
the interactions between cells, on communications between cells
or on the behavior of cells. The cytokines includes the interleukins,
lymphokines and cell signal molecules, such as tumor necrosis factor
and the interferons, which trigger inflammation and respond to infections.
sulfoxide (DMSO): A solvent that can be absorbed directly through
abbreviation for deoxyribonucleic acid, which makes up genes.
medium: A proprietary product commonly used in culturing cells.
Embryonic stem cells: Stem cells taken from an unborn fetus.
A laboratory-made agent similar to a normally existing substance
in the body that stimulates the production of blood cells. The colony-stimulating
factors (CSFs) include granulocyte colony-stimulating factors (G-CSF)
and granulocyte-macrophage colony-stimulating factors (GM-CSF).
A functional unit of heredity which is a segment of DNA located
in a specific site on a chromosome. A gene directs the formation
of an enzyme or other protein.
colony-forming cells: Progenitor cells from which all blood
Prepared to delay clotting.
Abbreviation for immunoglobulin G, a major class of immunoglobulins
found in the blood, including many of the most common antibodies
circulating in the blood. Also known as gamma globulin.
Interleukin 6. Aberrant production of IL6 by neoplastic cells has
been implicated as a strong contributory factor to the growth of
multiple myeloma and other B-cell dyscrasias, T-cell lymphoma, renal
and ovarian cell carcinomas, and Kaposi sarcoma. An IL6 promoter
polymorphism is associated with a lifetime risk of development of
Kaposi sarcoma in men infected with human immunodeficiency virus.
Ischemic stroke refers to strokes caused by thrombosis or embolism
and accounts for 80% of all strokes.
Removal of the blood to collect specific blood cells; the remaining
blood is returned to the body.
A type of white blood cell that surrounds and kills microorganisms,
removes dead cells, and stimulates the action of other immune system
cells. A type of large leukocyte that travels in the blood but can
leave the bloodstream and enter tissue; like other leukocytes, it
protects the body by digesting debris and foreign cells.
Refers to the cells that develop into connective tissue, blood
vessels, and lymphatic tissue.
cells: Cells having only one nucleus.
Stem cells that can give rise to several other cell types, but those
types are limited in number. An example of a multipotent stem cell
is a hematopoietic cell � a blood stem cell that can develop into
several types of blood cells, but cannot develop into brain cells
or other types of cells. At the end of the long series of cell divisions
that form the embryo are cells that are terminally differentiated,
or that are considered to be permanently committed to a specific
infarction: Destruction of heart tissue resulting from obstruction
of the blood supply to the heart muscle. In layman�s terms, a heart
blood cells: Blood cells circulating through the body.
The potential of a cell to develop into more than one type of mature
cell, depending on environment; capable of giving rise to most tissues
of an organism.
The reproduction or renewal of tissues, cells, etc., which have
been used up or destroyed.
Medicine: For our purposes, the use of stem cells or tissue
to regenerate other cells or tissue in the body.
cell: Cell of the body other than egg or sperm. Somatic cell
nuclear transfer: The transfer of a cell nucleus from a somatic
cell into an egg from which the nucleus has been removed.
cells: Cells that have the ability to divide for indefinite
periods in culture and to give rise to specialized cells.
A small lymphocyte developed in the thymus; it orchestrates the
immune system�s response to infected or malignant cells.
geometry: The geometry of cells in the blood in a three-dimensional
state (their natural state) as opposed to two-dimensional in a Petri
Having unlimited capability to produce all the cells and tissues
in the body.
is a Stem cell?
is a stem cell? Stem cells have the ability to divide for indefinite
periods in culture and to give rise to specialized cells. They are
best described in the context of normal human development. Human
development begins when a sperm fertilizes an egg and creates a
single cell that has the potential to form an entire organism. This
fertilized egg is totipotent, meaning that its potential is total.
In the first hours after fertilization, this cell divides into identical
means that these cells, if placed into a woman's uterus, have the
potential to develop into a fetus. In fact, identical twins develop
when two totipotent cells separate and develop into two individual,
genetically identical human beings. Approximately four days after
fertilization and after several cycles of cell division, these totipotent
cells begin to specialize, forming a hollow sphere of cells, called
a blastocyst. The blastocyst has an outer layer of cells and inside
the hollow sphere, there is a cluster of cells called the inner
outer layer of cells will go on to form the placenta and other supporting
tissues needed for fetal development in the uterus. The inner cell
mass cells will go on to form virtually all of the tissues of the
human body. Although the inner cell mass cells can form virtually
every type of cell found in the human body, they cannot form an
organism because they are unable to give rise to the placenta and
supporting tissues necessary for development in the human uterus.
These inner cell mass cells are pluripotent - they can give rise
to many types of cells but not all types of cells necessary for
fetal development. Because their potential is not total, they are
not totipotent and they are not embryos. In fact, if an inner cell
mass cell were placed into a woman's uterus, it would not develop
into a fetus.
pluripotent stem cells undergo further specialization into stem
cells that are committed to give rise to cells that have a particular
function. Examples of this include blood stem cells which give rise
to red blood cells, white blood cells and platelets; and skin stem
cells that give rise to the various types of skin cells. These more
specialized stem cells are called multipotent.
stem cells are extraordinarily important in early human development,
multipotent stem cells are also found in children and adults. For
example, consider one of the best understood stem cells, the blood
stem cell. Blood stem cells reside in the bone marrow of every child
and adult, and in fact, they can be found in very small numbers
circulating in the blood stream. Blood stem cells perform the critical
role of continually replenishing our supply of blood cells - red
blood cells, white blood cells, and platelets - throughout life.
A person cannot survive without blood stem cells.
are pluripotent stem cells derived?
present, human pluripotent cell lines have been developed from two
sources with methods previously developed in work with animal models.
In the work done by Dr. Thomson, pluripotent stem cells were isolated
directly from the inner cell mass of human embryos at the blastocyst
stage. Dr. Thomson received embryos from IVF (In Vitro Fertilization)
clinics-these embryos were in excess of the clinical need for infertility
treatment. The embryos were made for purposes of reproduction, not
research. Informed consent was obtained from the donor couples.
Dr. Thomson isolated the inner cell mass (see Figure III) and cultured
these cells producing a pluripotent stem cell line. In contrast,
Dr. Gearhart isolated pluripotent stem cells from fetal tissue obtained
from terminated pregnancies. Informed consent was obtained from
the donors after they had independently made the decision to terminate
their pregnancy. Dr. Gearhart took cells from the region of the
fetus that was destined to develop into the testes or the ovaries.
Although the cells developed in Dr. Gearhart's lab and Dr. Thomson's
lab were derived from different sources, they appear to be very
use of somatic cell nuclear transfer (SCNT) may be another way that
pluripotent stem cells could be isolated. In studies with animals
using SCNT, researchers take a normal animal egg cell and remove
the nucleus (cell structure containing the chromosomes). The material
left behind in the egg cell contains nutrients and other energy-producing
materials that are essential for embryo development. Then, using
carefully worked out laboratory conditions, a somatic cell - any
cell other than an egg or a sperm cell - is placed next to the egg
from which the nucleus had been removed, and the two are fused.
The resulting fused cell, and its immediate descendants, are believed
to have the full potential to develop into an entire animal, and
hence are totipotent. As described in Figure I, these totipotent
cells will soon form a blastocyst. Cells from the inner cell mass
of this blastocyst could, in theory, be used to develop pluripotent
stem cell lines. Indeed, any method by which a human blastocyst
is formed could potentially serve as a source of human pluripotent
Applications of Pluripotent Stem Cells
are several important reasons why the isolation of human pluripotent
stem cells is important to science and to advances in health care.
At the most fundamental level, pluripotent stem cells could help
us to understand the complex events that occur during human development.
A primary goal of this work would be the identification of the factors
involved in the cellular decision-making process that results in
cell specialization. We know that turning genes on and off is central
to this process, but we do not know much about these "decision-making"
genes or what turns them on or off. Some of our most serious medical
conditions, such as cancer and birth defects, are due to abnormal
cell specialization and cell division. A better understanding of
normal cell processes will allow us to further delineate the fundamental
errors that cause these often deadly illnesses.
pluripotent stem cell research could also dramatically change the
way we develop drugs and test them for safety. For example, new
medications could be initially tested using human cell lines. Cell
lines are currently used in this way (for example cancer cells).
Pluripotent stem cells would allow testing in more cell types. This
would not replace testing in whole animals and testing in human
beings, but it would streamline the process of drug development.
Only the drugs that are both safe and appear to have a beneficial
effect in cell line testing would graduate to further testing in
laboratory animals and human subjects.
the most far-reaching potential application of human pluripotent
stem cells is the generation of cells and tissue that could be used
for so-called "cell therapies." Many diseases and disorders result
from disruption of cellular function or destruction of tissues of
the body. Today, donated organs and tissues are often used to replace
ailing or destroyed tissue. Unfortunately, the number of people
suffering from these disorders far outstrips the number of organs
available for transplantation. Pluripotent stem cells, stimulated
to develop into specialized cells, offer the possibility of a renewable
source of replacement cells and tissue to treat a myriad of diseases,
conditions, and disabilities including Parkinson's and Alzheimer's
diseases, spinal cord injury, stroke, burns, heart disease, diabetes,
osteoarthritis and rheumatoid arthritis. There is almost no realm
of medicine that might not be touched by this innovation. Some details
of two of these examples follow.
of healthy heart muscle cells could provide new hope for patients
with chronic heart disease whose hearts can no longer pump adequately.
The hope is to develop heart muscle cells from human pluripotent
stem cells and transplant them into the failing heart muscle in
order to augment the function of the failing heart. Preliminary
work in mice and other animals has demonstrated that healthy heart
muscle cells transplanted into the heart successfully repopulate
the heart tissue and work together with the host cells. These experiments
show that this type of transplantation is feasible.
the many individuals who suffer from Type I diabetes, the production
of insulin by specialized pancreatic cells, called islet cells,
is disrupted. There is evidence that transplantation of either the
entire pancreas or isolated islet cells could mitigate the need
for insulin injections. Islet cell lines derived from human pluripotent
stem cells could be used for diabetes research and, ultimately,
this research shows extraordinary promise, there is much to be done
before we can realize these innovations. Technological challenges
remain before these discoveries can be incorporated into clinical
practice. These challenges, though significant, are not insurmountable.
we must do the basic research to understand the cellular events
that lead to cell specialization in the human, so that we can direct
these pluripotent stem cells to become the type(s) of tissue needed
before we can use these cells for transplantation, we must overcome
the well-known problem of immune rejection. Because human pluripotent
stem cells derived from embryos or fetal tissue would be genetically
different from the recipient, future research would need to focus
on modifying human pluripotent stem cells to minimize tissue incompatibility
or to create tissue banks with the most common tissue-type profiles.
use of somatic cell nuclear transfer (SCNT) would be another way
to overcome the problem of tissue incompatibility for some patients.
For example, consider a person with progressive heart failure. Using
SCNT, the nucleus of virtually any somatic cell from that patient
could be fused with a donor egg cell from which the nucleus had
been removed. With proper stimulation the cell would develop into
a blastocyst: cells from the inner cell mass could be taken to create
a culture of pluripotent cells. These cells could then be stimulated
to develop into heart muscle cells. Because the vast majority of
genetic information is contained in the nucleus, these cells would
be essentially identical genetically to the person with the failing
heart. When these heart muscle cells were transplanted back into
the patient, there would likely be no rejection and no need to expose
the patient to immune-suppressing drugs, which can have toxic effects.
noted earlier, multipotent stem cells can be found in some types
of adult tissue. In fact, stem cells are needed to replenish the
supply cells in our body that normally wear out. An example, which
was mentioned previously, is the blood stem cell.
stem cells have not been found for all types of adult tissue, but
discoveries in this area of research are increasing. For example,
until recently, it was thought that stem cells were not present
in the adult nervous system, but, in recent years, neuronal stem
cells have been isolated from the rat and mouse nervous systems.
The experience in humans is more limited. In humans, neuronal stem
cells have been isolated from fetal tissue and a kind of cell that
may be a neuronal stem cell has been isolated from adult brain tissue
that was surgically removed for the treatment of epilepsy.
adult stem cells have the same potential as pluripotent stem cells?
recently, there was little evidence in mammals that multipotent
cells such as blood stem cells could change course and produce skin
cells, liver cells or any cell other than a blood stem cell or a
specific type of blood cell; however, research in animals is leading
scientists to question this view.
animals, it has been shown that some adult stem cells previously
thought to be committed to the development of one line of specialized
cells are able to develop into other types of specialized cells.
For example, recent experiments in mice suggest that when neural
stem cells were placed into the bone marrow, they appeared to produce
a variety of blood cell types. In addition, studies with rats have
indicated that stem cells found in the bone marrow were able to
produce liver cells. These exciting findings suggest that even after
a stem cell has begun to specialize, the stem cell may, under certain
conditions, be more flexible than first thought. At this time, demonstration
of the flexibility of adult stem cells has been only observed in
animals and limited to a few tissue types.
the enormous promise of stem cells to the development of new therapies
for the most devastating diseases, it is important to simultaneously
pursue all lines of research. Science and scientists need to search
for the very best sources of these cells. When they are identified,
regardless of their sources, researchers will use them to pursue
the development of new cell therapies.
development of stem cell lines, both pluripotent and multipotent,
that may produce many tissues of the human body is an important
scientific breakthrough. It is not too unrealistic to say that this
research has the potential to revolutionize the practice of medicine
and improve the quality and length of life.