SCIENCE
Stem cells differ from other kinds of cells in the body. All stem cells—regardless of
their source—have three general properties: they are capable of dividing and
renewing themselves for long periods; they are unspecialised; and they can give rise
to specialised cell types.
Stem cells are capable of dividing and renewing themselves for long periods. Unlike
muscle cells, blood cells, or nerve cells—which do not normally replicate
themselves—stem cells may replicate many times, or proliferate. A starting
population of stem cells that proliferates for many months in the laboratory can yield
millions of cells. If the resulting cells continue to be unspecialised, like the parent
stem cells, the cells are said to be capable of long-term self-renewal.
Stem cells differ from other kinds of cells in the body. All stem cells—regardless of
their source—have three general properties: they are capable of dividing and
renewing themselves for long periods; they are unspecialised but can give rise to
(develop into) specialised cell types.
Stem cells are unspecialised. One of the fundamental properties of a stem cell is that
it does not have any tissue-specific structures that allow it to perform specialised
functions. For example, a stem cell cannot work with its neighbours to pump blood
through the body (like a heart muscle cell), and it cannot carry oxygen molecules
through the bloodstream (like a red blood cell). However, unspecialised stem cells
can give rise to specialised cells, including heart muscle cells, blood cells, or nerve
cells.
Stem cells can give rise to specialised cells. When unspecialised stem cells give rise to
specialised cells, the process is called differentiation. While differentiating, the cell
usually goes through several stages, becoming more specialised at each step.
Scientists are just beginning to understand the signals inside and outside cells that
trigger each stem of the differentiation process. The internal signals are controlled
by a cell's genes, which are interspersed across long strands of DNA, and carry coded
instructions for all cellular structures and functions. The external signals for cell
differentiation include chemicals secreted by other cells, physical contact with
neighbouring cells, and certain molecules in the microenvironment. The interaction
of signals during differentiation causes the cell's DNA to acquire epigenetic marks
that restrict DNA expression in the cell and can be passed on through cell division.
Stem cells are capable of dividing and renewing themselves for long periods. Unlike
muscle cells, blood cells, or nerve cells—which do not normally replicate
themselves—stem cells may replicate many times, or proliferate. A starting
population of stem cells that proliferates for many months in the laboratory can yield
millions of cells.
FUNCTION OF STEM CELLS
The functions of regenerative stem cells include the following:-
ANTI-INFLAMMATORY/IMMUNOMODULATION
In general, in vitro studies demonstrate that bone marrow-derived MSCs (BM-MSCs)
and adipose-derived MSC limit inflammatory responses and promote antiinflammatory pathways.
When present in an inflammatory environment, data demonstrates that BM-MSCs
may alter the cytokine secretion profile of dendritic cell (DC) subsets and T-cell
subsets causing a shift from a proinflammatory environment to an anti-inflammatory
or tolerant environment.
BM-MSCs do not express MHC class II antigens or costimulatory molecules and they
suppress T cell proliferation.
AD-MSC suppress mixed lymphocyte reactions and inhibits T cell proliferation
induced by a third cell type or by mitogenic factors.
Both types of MSC are able to control lethal graft versus host disease (GVHD) in mice
after haploidentical hematopoietic transplantation.
TROPHIC SUPPORT
Multiple studies demonstrate that MSCs secrete bioactive levels of cytokines and
growth factors that that support angiogenesis, tissue remodeling, differentiation,
and antiapoptotic events.
D-MSCs secrete a number of angiogenesis-related cytokines such as:
Vascular endothelial growth factor (VEGF)
Hepatocyte growth factor (HGF)
Basic fibroblast growth factor (bFGF)
Granulocyte-macrophage colony stimulating factor (GM-CSF)
Transforming growth factor – β
DIFFERENTIATION
Adipose derived MSC studies demonstrate a diverse plasticity, including
differentiation into adipo-, osteo-, chondro-, myo-, cardiomyo-, endothelial, hepato-,
neuro-, epithelial and hematopoietic lineages, similar to that described for bone
marrow derived MSC. These data are supported by in vivo experiments and
functional studies that demonstrated the regenerative capacity of adipose-derived
MSCs to repair damaged or diseased tissue via transplant engraftment and
differentiation.
Awad and colleagues reported significant improvements using autologous MSC
delivery in a rabbit Achilles tendon repair model compared to cell-free collagen
control rabbits.
Nixon and colleagues demonstrated statistically significant improvement in
histological repair of a collagenase-induced injury in the superficial digital flexor
tendonitis in horses treated with autologous regenerative cells harvested from fat.
In a caprine model of traumatic joint injury, BM- MSCs delivered intra-articularly
engrafted and repaired meniscal tissue, leading to a statistically significant reduction
in the progression of osteoarthritis.
Multiple studies demonstrate in vivo bone regeneration and repair in animal models.
Bruder and colleagues demonstrated in two studies that BM-MSCs could be used to
repair a critical defect in a non-union fracture model in dogs.
Cowan and colleagues demonstrated that AD-MSCs heal a critical-size mouse
calvarial defect in which there was increased bone formation and mineralization
compared to controls.
A human clinical case showed a dramatic regeneration of the calvarium in a young
girl with severe traumatic damage.
In a rodent cerebral infarct model, Jeong and colleagues demonstrated that infracted
rats administered magnetically labeled AD-MSC administered two weeks after the
creation of an infarct experienced restoration of locomotor function compared to
controls.
HOMING
Homing (chemotaxis) is an event by which a cell migrates from one area of the body
to a distant site where it may be needed for a given physiological event. Homing is
an important function of MSCs and other progenitor cells and one mechanism by
which intravenous or parenteral administration of MSCs permits an autotransplanted therapeutic cell to effectively target a specific area of pathology.
Nilsson and colleagues demonstrated that labeled cells of bone lineage injected
intravenously into mice can engraft, form bone, and give rise to osteocytes and bone
lining cells detectable on the mouse femur.
Chen and colleagues performed peripheral intravenous experiments using a cerebral
arterial occlusion model of stroke and demonstrated that labeled BM-MSCs
administered hours and 7 days post-injury has demonstrated migration to the area
of injury as well as a dramatic reduction in stoke infarct size.
REVASCULARISATION
Adipose derived regenerative cells contain endothelial progenitor cells and MSCs
that assist in angiogenesis and neovascularisation by the secretion of cytokines, such
as hepatic growth factor (HGF), vascular endothelial growth factor (VEGF), placental
growth factor (PGF), transforming growth factor (TGFβ), fibroblast growth factor
(FGF-2), and angiopoietin.
Chen and colleagues examined the effect of intravenous administration of BM-MSCs
after cerebral arterial occlusion in the rat and demonstrated new capillary formation,
increased vessel formation and increased VEGF (vascular endothelial growth factor)
expression in the areas of the lesion.
In an in vivo model of hind limb eschemia, intravenous injection of AD-MSC were
associated with an increase in blood flow and capillary density and incorporation of
the cells in the leg vasculature.
Rehman and colleagues demonstrated that nude mice with ischemic hind limbs
demonstrated marked perfusion improvement when treated with human AD-MSC.
ANTI-APOPTOSIS:
Apoptosis is defined as a programmed cell death or “cell suicide”, an event that is
genetically controlled. Under normal conditions, apoptosis determines the lifespan
and coordinated removal of cells. Unlike necrosis, apoptotic cells are typically intact
during their removal (phagocytosis).
Rehman and colleagues demonstrated this effect in acutely injured tissue denied
critical blood-flow resulting in ischemia. AD-MSC significantly reduced endothelial
cell apoptosis.
Kortesidis and colleagues also demonstrate that BM-MSCs express factors that
support cell survival and avoid apoptosis thereby preserving cells that would
otherwise be destroyed.
GENERAL OVERVIEW
Stem cells differ from other kinds of cells in the body. All stem cells—regardless of
their source—have three general properties: they are capable of dividing and
renewing themselves for long periods; they are unspecialised; and they can give rise
to specialized cell types.
Stem cells are capable of dividing and renewing themselves for long periods. Unlike
muscle cells, blood cells, or nerve cells—which do not normally replicate
themselves—stem cells may replicate many times, or proliferate. A starting
population of stem cells that proliferates for many months in the laboratory can yield
millions of cells. If the resulting cells continue to be unspecialised, like the parent
stem cells, the cells are said to be capable of long-term self-renewal.
Scientists are trying to understand two fundamental properties of stem cells that
relate to their long-term self-renewal:
Why can embryonic stem cells proliferate for a year or more in the laboratory
without differentiating, but most non-embryonic stem cells cannot; and
What are the factors in living organisms that normally regulate stem cell proliferation
and self-renewal?
The specific factors and conditions that allow stem cells to remain unspecialised are
of great interest to scientists. It has taken scientists many years of trial and error to
learn to derive and maintain stem cells in the laboratory without them
spontaneously differentiating into specific cell types. For example, it took two
decades to learn how to grow human embryonic stem cells in the laboratory
following the development of conditions for growing mouse stem cells. Therefore,
understanding the signals in a mature organism that cause a stem cell population to
proliferate and remain unspecialised until the cells are needed. Such information is
critical for scientists to be able to grow large numbers of unspecialised stem cells in
the laboratory for further experimentation.
Stem cells are unspecialised. One of the fundamental properties of a stem cell is that
it does not have any tissue-specific structures that allow it to perform specialized
functions. For example, a stem cell cannot work with its neighbours to pump blood
through the body (like a heart muscle cell), and it cannot carry oxygen molecules
through the bloodstream (like a red blood cell). However, unspecialised stem cells
can give rise to specialized cells, including heart muscle cells, blood cells, or nerve
cells.
Stem cells can give rise to specialized cells. When unspecialised stem cells give rise to
specialized cells, the process is called differentiation. While differentiating, the cell
usually goes through several stages, becoming more specialized at each step.
Scientists are just beginning to understand the signals inside and outside cells that
trigger each stem of the differentiation process. The internal signals are controlled
by a cell's genes, which are interspersed across long strands of DNA, and carry coded
instructions for all cellular structures and functions. The external signals for cell
differentiation include chemicals secreted by other cells, physical contact with
neighbouring cells, and certain molecules in the micro-environment. The interaction
of signals during differentiation causes the cell's DNA to acquire epigenetic marks
that restrict DNA expression in the cell and can be passed on through cell division.
Many questions about stem cell differentiation remain. For example, are the internal
and external signals for cell differentiation similar for all kinds of stem cells? Can
specific sets of signals be identified that promote differentiation into specific cell
types? Addressing these questions may lead scientists to find new ways to control
stem cell differentiation in the laboratory, thereby growing cells or tissues that can
be used for specific purposes such as cell-based therapies or drug screening.
Adult stem cells typically generate the cell types of the tissue in which they reside.
For example, a blood-forming adult stem cell in the bone marrow normally gives rise
to the many types of blood cells. It is generally accepted that a blood-forming cell in
the bone marrow—which is called a hematopoietic stem cell—cannot give rise to the
cells of a very different tissue, such as nerve cells in the brain. Experiments over the
last several years have purported to show that stem cells from one tissue may give
rise to cell types of a completely different tissue. This remains an area of great
debate within the research community. This controversy demonstrates the
challenges of studying adult stem cells and suggests that additional research using
adult stem cells is necessary to understand their full potential as future therapies.
ADULT STEM CELLS
BACKGROUND
Adult stem cells (‘ASC’) are unspecialized or undifferentiated cells found throughout
the body after embryonic development. ASC’s can be found in juvenile as well as
adult animals and humans.
The primary roles of adult stem cells in a living organism are to maintain and repair
the tissue in which they are found.
The history of research on adult stem cells began about 50 years ago. In the 1950s,
researchers discovered that the bone marrow contains at least two kinds of stem
cells. One population, called hematopoietic stem cells, forms all the types of blood
cells in the body.
A second population, called stromal stem cells (also called mesenchymal stem cells,
or skeletal stem cells by some), were discovered a few years later. These nonhematopoietic stem cells can generate bone, cartilage, fat, cells that support the
formation of blood, and fibrous connective tissue.
An adult stem cell can be found among differentiated cells in a tissue or organ, and
can renew itself and can differentiate to yield some or all of the major specialized
cell types of the tissue or organ. ASC’s are found in many adult tissues including the
bone marrow and adipose tissue.
ASC multiply by cell division to replenish dying cells and regenerate damaged tissues.
Scientific interest in adult stem cells has centred on their ability to divide or selfrenew indefinitely, and generate all the cell types of the organ from which they
originate, potentially regenerating the entire organ from a few cells.
Adult stem cells (ASCs) lie dormant (quiescent) and non-dividing within different
adult human tissues until they are activated by signals from diseased, dying or
damaged tissue to not only divide to form more stem cells, but also to differentiate
into different types of specialised cells to replenish or regenerate these affected
cells.
ASCs were generally thought to be 'multipotent' lineage-restricted cells with the
ability to only differentiate into types of cells predetermined by the germ layer-origin
of the tissue within which they reside. However, in vitro studies have shown that,
given the right conditions, some ASCs can differentiate into cell types of germ-origin
different to their tissue of origin. This is called Trans-differentiation or Plasticity. This
makes these ASCs 'pluripotent' and hence very attractive in on-going stem cell
research to find ways of culturing and transplanting healthy cells to replace diseased,
damaged or dying tissues.
Originally identified as a source of osteoprogenitor cells, MSCs differentiate into
adipocytes, chondrocytes, osteoblasts, and myoblasts in vitro (Hauner et al., 1987 ;
Grigoradis et al., 1988 ; Wakitani et al., 1995 ; Ferrari et al., 1998 ; Johnstone et al.,
1998 ; Pittenger et al., 1999 ) and undergo differentiation in vivo (Benayahu et al.,
1989 ; Bruder et al., 1998a ), making these stem cells promising candidates for
mesodermal defect repair and disease management.
ASCs can be described in a number of ways depending on their potency, germ layer
of origin, or their tissue of origin. For example, ASCs present in adipose tissue may be
called Multipotent, Mesenchymal, Adipose-derived, ASCs.
Adult stem cell treatments have been successfully used for many years to treat
leukemia and related bone/blood cancers through bone marrow transplants in
humans. Adult stem cells have also been used extensively in veterinary medicine to
treat arthritis in dogs as well as tendon and ligament injuries in horses.
The use of adult stem cells in research and therapy is not as controversial as
embryonic stem cells, because the production of adult stem cells does not require
the destruction of an embryo.
Given both the clinical and ethical issues surrounding the use of embryonic stem
cells, Australian Veterinary Stem Cells has been pursuing the use of adult stem cells
from adipose tissue ‘ADMSC’s) in the treatment of a number of conditions in the
veterinary setting.
Adipose-derived adult mesenchymal stem cells (ADMSC) are multipotent and can
differentiate into tendon, ligament, bone, cartilage, cardiac, nerve, muscle, blood
vessels, fat, and liver tissue (see figure below). The stromal fraction that is harvested
from adipose tissue is a heterogeneous mixture of regenerative cells (see below).
Adipose tissue represents a source of stem cells that is having far-reaching effects in
a large number of fields of medicine. ADMSC cells have potential applications for the
repair and regeneration of acute and chronically damaged tissues.
ADULT ADIPOSE DERIVED STEM CELLS
Adipose tissue represents a source of stem cells that is having far-reaching effects in
a large number of fields of medicine. ADMSC cells have potential applications for the
repair and regeneration of acute and chronically damaged tissues.
Adipose-derived adult mesenchymal stem cells (ADMSC) are multipotent and can
differentiate into tendon, ligament, bone, cartilage, cardiac, nerve, muscle, blood
vessels, fat, and liver tissue (see figure below).
AVSC can supply therapies based on high concentration 'off the shelf" pure cultured
stem cells or alternatively therapies based on the use of an animal’s own stromal
vascular fraction (‘SVF’).
The stromal fraction that is harvested from adipose tissue is a heterogeneous
mixture of regenerative cells (see below).
WHAT ARE ADULT STEM CELLS
The primary roles of adult stem cells in a living organism are to maintain and repair
the tissue in which they are found.
Adult stem cells (‘ASC’) are unspecialized or undifferentiated cells found throughout
the body after embryonic development. ASC’s can be found in juvenile as well as
adult animals and humans.
An adult stem c ell can be found among differentiated cells in a tissue or organ, and
can renew itself and can differentiate to yield some or all of the major specialized
cell types of the tissue or organ. ASC multiply by cell division to replenish dying cells
and regenerate damaged tissues.
Scientific interest in adult stem cells has centered on their ability to divide or selfrenew indefinitely, and generate all the cell types of the organ from which they
originate, potentially regenerating the entire organ from a few cells.
Stem cell division and same. A - stem cells; B - progenitor cell; C - differentiated cell;
1 - symmetric stem cell division; 2 - asymmetric stem cell division; 3 - progenitor
division; 4 - terminal differentiation
Adult stem cells (ASCs) lie dormant (quiescent) and non-dividing within different
adult human tissues until they are activated by signals from diseased, dying or
damaged tissue to not only divide to form more stem cells, but also to differentiate
into different types of specialized cells to replenish or regenerate these affected
cells.
ASCs were generally thought to be 'multipotent' lineage-restricted cells with the
ability to only differentiate into types of cells predetermined by the germ layer-origin
of the tissue within which they reside. However, in vitro studies have shown that,
given the right conditions, some ASCs can differentiate into cell types of germ-origin
different to their tissue of origin. This is called Trans-differentiation or Plasticity. 4 , 5
, This makes these ASCs 'pluripotent' and hence very attractive in on-going stem cell
research to find ways of culturing and transplanting healthy cells to replace diseased,
damaged or dying tissues. 6.
Scientists also use the term somatic stem cell instead of adult stem cell, where
somatic refers to cells of the body (not the germ cells, sperm or eggs).
ASCs can be described in a number of ways depending on their potency, germ layer
of origin, or their tissue of origin. For example, ASCs present in adipose tissue may be
called Multipotent, Mesenchymal, Adipose-derived, ASCs.
Adult stem cell treatments have been successfully used for many years to treat
leukemia and related bone/blood cancers through bone marrow transplants in
humans. Adult stem cells have also been used extensively in veterinary medicine to
treat arthritis in dogs as well as tendon and ligament injuries in horses.
PROPERTIES OF ADULT STEM CELLS
The rigorous definition of a stem cell requires that it possesses two properties:
Self-renewal which is the ability to go through numerous cycles of cell division while
still maintaining its undifferentiated state
Multipotency or multidifferentiative potential which is the ability to generate
progeny of several distinct cell types, (for example glial cells and neurons) as
opposed to unipotency which is the term for cells that are restricted to producing a
single-cell type.
(However, some researchers do not consider multipotency to be essential, and
believe that unipotent self-renewing stem cells can exist)
LINEAGE
To ensure self-renewal, stem cells undergo two types of cell division (see Stem cell
division and differentiation diagram). Symmetric division gives rise to two identical
daughter cells, both endowed with stem cell properties, whereas asymmetric
division produces only one stem cell and a progenitor cell with limited self-renewal
potential. Progenitors can go through several rounds of cell division before finally
differentiating into a mature cell. It is believed that the molecular distinction
between symmetric and asymmetric divisions lies in differential segregation of cell
membrane proteins (such as receptors) between the daughter cells.
MULTI-DRUG RESISTANCE
Adult stem cells express transporters of the ATP-binding cassette family that actively
pump a diversity of organic molecules out of the cell.[1] Many pharmaceuticals are
exported by these transporters conferring multidrug resistance onto the cell. This
complicates the design of drugs, for instance neural stem cell targeted therapies for
the treatment of clinical depression.
SIGNALING PATHWAYS
Adult stem cell research has been focused on uncovering the general molecular
mechanisms that control their self-renewal and differentiation.
NOTCH
The Notch pathway has been known to developmental biologists for decades. Its role
in control of stem cell proliferation has now been demonstrated for several cell types
including haematopoietic, neural and mammary[2] stem cells.
WNT
These developmental pathways are also strongly implicated as stem cell
regulators.[3]
OTHER STEM CELLS
Stem cells have the remarkable potential to develop into many different cell types in
the body during early life and growth. In addition, in many tissues they serve as a
sort of internal repair system, dividing essentially without limit to replenish other
cells as long as the person or animal is still alive. When a stem cell divides, each new
cell has the potential either to remain a stem cell or become another type of cell
with a more specialized function, such as a muscle cell, a red blood cell, or a brain
cell.
Stem cells are distinguished from other cell types by two important characteristics.
First, they are unspecialised cells capable of renewing themselves through cell
division, sometimes after long periods of inactivity. Second, under certain physiologic
or experimental conditions, they can be induced to become tissue- or organ-specific
cells with special functions. In some organs, such as the gut and bone marrow, stem
cells regularly divide to repair and replace worn out or damaged tissues. In other
organs, however, such as the pancreas and the heart, stem cells only divide under
special conditions.
Until recently, scientists primarily worked with two kinds of stem cells from animals
and humans: embryonic stem cells and non-embryonic "somatic" or "adult" stem
cells. The functions and characteristics of these cells will be explained in this
document. Scientists discovered ways to derive embryonic stem cells from early
mouse embryos nearly 30 years ago, in 1981. The detailed study of the biology of
mouse stem cells led to the discovery, in 1998, of a method to derive stem cells from
human embryos and grow the cells in the laboratory. These cells are called human
embryonic stem cells. The embryos used in these studies were created for
reproductive purposes through in vitro fertilization procedures. When they were no
longer needed for that purpose, they were donated for research with the informed
consent of the donor. In 2006, researchers made another breakthrough by
identifying conditions that would allow some specialized adult cells to be
"reprogrammed" genetically to assume a stem cell-like state. This new type of stem
cell, called induced pluripotent stem cells (iPSCs), will be discussed in a later section
of this document.
Stem cells are important for living organisms for many reasons. In the 3- to 5-day-old
embryo, called a blastocyst, the inner cells give rise to the entire body of the
organism, including all of the many specialized cell types and organs such as the
heart, lung, skin, sperm, eggs and other tissues. In some adult tissues, such as bone
marrow, muscle, and brain, discrete populations of adult stem cells generate
replacements for cells that are lost through normal wear and tear, injury, or disease.
Given their unique regenerative abilities, stem cells offer new potentials for treating
diseases such as diabetes, and heart disease. However, much work remains to be
done in the laboratory and the clinic to understand how to use these cells for cellbased therapies to treat disease, which is also referred to as regenerative or
reparative medicine.
Stem Cells are multipotent and can differentiate into tendon, ligament, bone,
cartilage, cardiac, nerve, muscle, blood vessels, fat, and liver tissue22, 23 (see figure
below).
SIMILARITIES AND DIFFERENCES BETWEEN EMBRYONIC AND ADULT
STEM CELLS
Human embryonic and adult stem cells each have advantages and disadvantages
regarding potential use for cell-based regenerative therapies.
Scientists believe that tissues derived from embryonic and adult stem cells differ in
the likelihood of being rejected after transplantation.
Adult stem cells (‘ASC’s) are present in all living humans (and animals) and as such do
not pose the same medical problems as embryonic stem cells. For instance, ASCs
from bone marrow have been successfully transplanted in sufferers of leukemia and
related cancers for many years now. In addition, adult mesenchymal stem cells (eg
from adipose tissue) are immuno-privileged cells that even have the ability to be
transplanted – without immune rejection.
The use of adult stem cells and tissues derived from the patient's own adult stem
cells means that the cells are less likely to be rejected by the immune system. This is
because a patient's own cells can be expanded in culture, coaxed into assuming a
specific cell type (differentiation), and then reintroduced into the patient. This
represents a significant advantage, as immune rejection of embryonic stem cells can
be circumvented only by continuous administration of immunosuppressive drugs,
and the drugs themselves may cause deleterious side effects.
In addition, adult mesenchymal stem cells (eg from adipose tissue) are immuneprivileged and as such ‘foreign’ cells (cells from a donor) can be transplanted without
rejection by a ‘recipient.
One other possible difference between adult and embryonic stem cells is in their
possible different abilities in the number and type of differentiated cell types they
can become. Embryonic stem cells can become all cell types of the body because
they are pluripotent. Adult stem cells may be limited in their ability to differentiate
into different cell types from their tissue of origin.
There are however still unsolved medical problems concerning the therapeutic use
of embryonic stem cells. The ability of embryonic stem cells to form teratomas is just
one of the obstacles confronting the use of embryonic stem cells.
A further problem with embryonic stem cells is that they can only be obtained by
destroying a human embryo. This poses ethical and religious issues. However, there
are no ethical issues with the use of Adult Stem Cells (‘ASC’s) because these cells can
be obtained from adult human tissue; for example from adipose (fat) tissue.
PLURIPOTENCY
Discoveries in recent years have suggested that adult stem cells might have the
ability to differentiate into cell types from different germ layers. For instance, neural
stem cells from the brain, which are derived from ectoderm, can differentiate into
ectoderm, mesoderm and endoderm.
Stem cells from the bone marrow, which is derived from mesoderm, can
differentiate into liver, lung, GI tract and skin, which are derived from endoderm and
mesoderm. This phenomenon is referred to as stem cell transdifferentiation or
plasticity. It can be induced by modifying the growth medium when stem cells are
cultured in vitro or transplanting them to an organ of the body different from the
one they were originally isolated from.
More recent findings suggest that pluripotent stem cells may reside in adult tissues
in a dormant state. These cells are referred to as "very small embryonic like" -"VSEL"
stem cells, and display pluripotency in vitro. As VSEL cells are present in virtually all
adult tissues, including lung, brain, kidneys, muscles, and pancreas. Co-purification of
VSEL cells with other populations of adult stem cells may explain the apparent
pluripotency of adult stem cell populations.
There is however not yet a consensus among biologists on the prevalence and
physiological and therapeutic relevance of stem cell plasticity.
INDUCED PLURIPOTENT STEM CELLS
Induced pluripotent stem cells (iPSCs) are adult cells that have been genetically
reprogrammed to an embryonic stem cell–like state by being forced to express genes
and factors important for maintaining the defining properties of embryonic stem
cells. Although these cells meet the defining criteria for pluripotent stem cells, it is
not known if iPSCs and embryonic stem cells differ in clinically significant ways.
Mouse iPSCs were first reported in 2006, and human iPSCs were first reported in late
2007. Mouse iPSCs demonstrate important characteristics of pluripotent stem cells,
including expressing stem cell markers, forming tumors containing cells from all
three germ layers, and being able to contribute to many different tissues when
injected into mouse embryos at a very early stage in development.
Human iPSCs also express stem cell markers and are capable of generating cells
characteristic of all three germ layers.
Although additional research is needed, iPSCs are already useful tools for drug
development and modeling of diseases, and scientists hope to use them in
transplantation medicine. Viruses are currently used to introduce the
reprogramming factors into adult cells, and this process must be carefully controlled
and tested before the technique can lead to useful treatments for humans. In animal
studies, the virus used to introduce the stem cell factors sometimes causes cancers.
Researchers are currently investigating non-viral delivery strategies. In any case, this
breakthrough discovery has created a powerful new way to "de-differentiate" cells
whose developmental fates had been previously assumed to be determined. In
addition, tissues derived from iPSCs will be a nearly identical match to the cell donor
and thus probably avoid rejection by the immune system. The iPSC strategy creates
pluripotent stem cells that, together with studies of other types of pluripotent stem
cells, will help researchers learn how to reprogram cells to repair damaged tissues in
the human body.
RESEARCH ON ADULT STEM CELLS ('ASC'S)
AVSC, through arrangements with Monash Immunology and stem Cell Laboratories
(‘MISCL’) - www.med.monash.edu.au/miscl - at Monash University (Melbourne) has
been developing stem cell products for veterinary treatments. AVSC believes that in
regard to a number of therapeutic conditions, stem cell treatments will be more
effective than traditional treatment options currently available.
The history of research on adult stem cells began about 50 years ago. In the 1950s,
researchers discovered that the bone marrow contains at least two kinds of stem
cells. One population, called hematopoietic stem cells, forms all the types of blood
cells in the body. A second population, called bone marrow stromal stem cells (also
called mesenchymal stem cells, or skeletal stem cells by some), were discovered a
few years later. These non-hematopoietic stem cells make up a small proportion of
the stromal cell population in the bone marrow, and can generate bone, cartilage,
fat, cells that support the formation of blood, and fibrous connective tissue.
Scientists have found adult stem cells in many more tissues than they once thought
possible. This finding has led researchers and clinicians to ask whether adult stem
cells could be used for transplants. In fact, adult hematopoietic, or blood-forming,
stem cells from bone marrow have been used in transplants for 40 years. Scientists
now have evidence that stem cells exist in the brain and the heart. If the
differentiation of adult stem cells can be controlled in the laboratory, these cells may
become the basis of transplantation-based therapies.
In the 1960s, scientists who were studying rats discovered two regions of the brain
that contained dividing cells that ultimately become nerve cells. Despite these
reports, most scientists believed that the adult brain could not generate new nerve
cells. It was not until the 1990s that scientists agreed that the adult brain does
contain stem cells that are able to generate the brain's three major cell types—
astrocytes and oligodendrocytes, which are non-neuronal cells, and neurons, or
nerve cells.
CLINICAL TRIALS
Magellan is dedicated to the ethical development and clinical application of stem cell
therapies.
In partnership with the Melbourne Stem Cell Centre, Magellan is currently a number
of fully funded clinical trials re the use of stem cells to treat musculo-skeletal
conditions – including osteoarthritis and traumatic knee cartilage injuries (use of
stem cells in association with arthroscopic procedures).
SAFETY
Based upon current clinical trial outcomes, mesenchymal stem cell therapies are
considered to be safe.
There are now close to 400 trials using mesenchymal stem cells registered with the
U.S. National Institutes of Health. Over 30 of these are focused on musculoskeletal
disease and most of these are treating osteoarthritis.
A recent review of trials involving a total of 1012 participants receiving stem cell
therapy for various clinical conditions including Ischaemic Stroke, Crohn’s disease,
cardiomyopathy, Ischaemic Heart Disease and graft versus host disease, did not
identify any significant adverse events other than transient elevation of
temperature/fever (Lalu et al, 2012). A further systematic review of intra-articular
injections of expanded mesenchymal stem cells in over 800 patients showed
evidence of safety with a period of self- limiting knee discomfort being the only
appreciable side effect (Peeters et al, 2012)
Patients were followed up in some studies for over 90 months. No association has
been made between mesenchymal stem cell therapy and adverse events such as
infection, malignancy or death.