Adult stem cells are undifferentiated cells found throughout the body after embryonic development that divide to replenish dying cells and regenerate damaged tissues. Also known as somatic (from Greek Σωματικóς, of the body) stem cells, they can be found in children, as well as adults.
Research into adult stem cells has been fueled by their abilities to divide or self-renew indefinitely and generate all the cell types of the organ from which they originate — potentially regenerating the entire organ from a few cells. Unlike embryonic stem cells, the use of adult stem cells in research and therapy is not controversial because the production of adult stem cells does not require the creation or destruction of an embryo. Adult stem cells can be isolated from a tissue sample obtained from an adult. They have mainly been studied in humans and model organisms such as mice and rats.
Adult stem cell therapies
Due to the ability of adult stem cells to be cut out from the patient, their therapeutic potential is the focus of much research. Adult stem cells, similar to embryonic stem cells, have the ability to differentiate into more than one cell type, but unlike embryonic stem cells they are often restricted to certain lineages. The ability of a stem cell of one lineage to become another lineage is called transdifferentiation
. Different types of adult stem cells are capable of transdifferentiation more than others, and for many there is no evidence of its occurrence. Consequently, adult stem therapies require a stem cell source of the specific lineage needed and harvesting and or culturing them up to the numbers required is a challenge.
Pluripotent stem cells can be found in a number of tissues including umbilical cord blood. Using genetic reprogramming, pluripotent stem cells equivalent to embryonic stem cells have been derived from human adult skin tissue. Other adult stem cells are lineage-restricted (multipotent) and are generally referred to by their tissue origin (mesenchymal stem cell, adipose-derived stem cell, endothelial stem cell, etc.).
A great deal of adult stem cell research has focused on clarifying their capacity to divide or self-renew indefinitely and their differentiation potential. In mice, pluripotent stem cells can be directly generated from adult fibroblast cultures.
Adult stem cell treatments have been used for many years to treat successfully leukemia and related bone/blood cancers through bone marrow transplants. 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. Consequently, more US government funding is being provided for adult stem cell research.
Adult Stem Cell and Cancer
In recent years, the concept of adult stem cells has grown. There is now a theory that stem cells reside in many adult tissues and that these unique reservoirs of adult stem cells are not only responsible for the normal reparative and regenerative processes but are also considered to be a prime target for genetic and epigenetic changes culminating in many abnormal conditions including cancer
The rigorous definition of a stem cell
requires that it possesses two properties:
- Self-renewal - the ability to go through numerous cycles of cell division while maintaining the undifferentiated state.
- Multipotency or multidifferentiative potential - the ability to generate progeny of several distinct cell types, for example both glial cells and neurons, opposed to unipotency - restriction to a single-cell type. Some researchers do not consider this property essential and believe that unipotent self-renewing stem cells can exist.
These properties can be illustrated with relative ease in vitro, using methods such as clonogenic assays, where the progeny of single cell is characterized. However, in vitro cell culture conditions can alter the behavior of cells. Proving that a particular subpopulation of cells possesses stem cell properties in vivo is challenging. Considerable debate exists whether some proposed cell populations in the adult are indeed stem cells.
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. Asymmetric division, on the other hand, produces only one stem cell and a progenitor cell
with limited self-renewal potential. Progentiors can go through several rounds of cell division before terminally 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.
Adult stem cells express transporters
of the ATP-binding cassette family
that actively pump
a diversity of organic molecules out of the cell. 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
Adult stem cell research has been focused on uncovering the general molecular mechanisms that control their self-renewal and differentiation.
- The transcriptional repressor Bmi-1 is one of the Polycomb-group proteins that was discovered as a common oncogene activated in lymphoma and later shown to specifically regulate HSCs. The role of Bmi-1 has also been illustrated in neural stem cells.
- 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 stem cells.
- These developmental pathways are also strongly implicated as stem cell regulators.
Under special conditions tissue-specific adult stem cells can generate a whole spectrum of cell types
of other tissues, even crossing germ layers
. 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. There is yet no consensus among biologists on the prevalence and physiological and therapeutic relevance of stem cell plasticity.
Adipose derived adult stem cells
Adipose-derived stem cells (ASCs) have also been isolated from human fat
, usually by method of liposuction
. This cell population seems to be similar in many ways to mesenchymal stem cells
(MSCs) derived from bone marrow. However, it is possible to isolate many more cells from adipose tissue and the harvest procedure itself is less painful than the harvest of bone marrow. Human ASCs have been shown to differentiate in the lab into bone
, fat, and muscle
, while ASCs from rats have been converted to neurons, which makes ASCs a possible source for future applications in the clinic. In support of this, current studies in animals suggest that ASCs might be able to repair significant bony defects and ASCs have been recently used to successfully repair a large cranial
defect in a human patient. ASCs are currently in use in veterinary medicine in horses and dogs, typically to aid in the repair of damaged tendons or ligaments, but also in joints.
Induced pluripotent stem cells derived from epithelial cells
These are not adult stem cells, but rather reprogrammed epithelial cells with pluripotent capabilities. Using genetic reprogramming with protein transcription factors, pluripotent stem cells equivalent to embryonic stem cells have been derived from human adult skin tissue. Shinya Yamanaka and his colleagues at Kyoto University used the transcription factors Oct3/4, Sox2, c-Myc, and Klf4 in their experiments on cells from human faces. Junying Yu, James Thomson, and their colleagues at the University of Wisconsin-Madison used a different set of factors, Oct4, Sox2, Nanog and Lin28 , and carried out their experiments using cells from human foreskin.
As a result of the success of these experiments, Ian Wilmut, who helped create the first cloned animal Dolly the Sheep, has announced that he will abandon theraputic cloning as an avenue of research.
Haematopoietic stem cells
Haematopoietic stem cells give rise to all the blood cell types and are found in the bone marrow.
Mammary stem cells
Mammary stem cells provide the source of cells for growth of the mammary gland
during puberty and gestation
and play an important role in carcinogenesis
of the breast. Mammary stem cells have been isolated from human and mouse tissue as well as from cell lines
derived from the mammary gland. A single such cell can give rise to both luminal
and myoepithelial cell
types of the gland and has been shown to regenerate the entire organ in mice.
Mesenchymal stem cells
Mesenchymal stem cells differentiate into connective tissue, and are found in the bone marrow.
Endothelial stem cells
Neural stem cells
The existence of stem cells in the adult brain has been postulated following the discovery that the process of neurogenesis
, birth of new neurons
, continues into adulthood in rats. It has since been shown that new neurons are generated in adult mice, songbirds and primates, including humans. Normally adult neurogenesis is restricted to the subventricular zone
, which lines the lateral ventricles
of the brain, and the dentate gyrus
of the hippocampal formation
. Although the generation of new neurons in the hippocampus
is well established, the presence of true self-renewing stem cells there has been debated. Under certain circumstances, such as following tissue damage in ischemia
, neurogenesis can be induced in other brain regions, including the neocortex
Neural stem cells are commonly cultured in vitro as so called neurospheres - floating heterogeneous aggregates of cells, containing a large proportion of stem cells. They can be propagated for extended periods of time and differentiated into both neuronal and glia cells, and therefore behave as stem cells. However, some recent studies suggest that this behaviour is induced by the culture conditions in progenitor cells, the progeny of stem cell division that normally undergo a strictly limited number of replication cycles in vivo. Furthermore, neurosphere-derived cells do not behave as stem cells when transplanted back into the brain.
Neural stem cells share many properties with haematopoietic stem cells (HSCs). Remarkably, when injected into the blood, neurosphere-derived cells differentiate into various cell types of the immune system. Cells that resemble neural stem cells have been found in the bone marrow, the home of HSCs. It has been suggested that new neurons in the dentate gyrus arise from circulating HCSs. Indeed, newborn cells first appear in the dentate in the heavily vascularised subgranular zone immediately adjacent to blood vessels.
Olfactory adult stem cells
Olfactory adult stem cells have been successfully harvested from the human olfactory mucosa cells, the lining of the nose
involved in the sense of smell.
- Adult stem cells isolated from the olfactory mucosa (cells lining the inside of the nose involved in the sense of smell) have the ability to develop into many different cell types if they are given the right chemical environment.
- These adult olfactory stem cells appear to have the same ability as embryonic stem cells in giving rise to many different cell types but have the advantage that they can be obtained from all individuals, even older people who might be most in need of stem cell therapies.
Olfactory stem cells hold potential for therapeutic applications. Thanks to their location they can be harvested with ease without harm to the patient in contrast to neural stem cells.
Multipotent stem cells with a claimed equivalency to embryonic stem cells have been derived from spermatogonial progenitor cells found in the testicles
of laboratory mice by scientists in Germany
and the United States
, and, a year later, researchers from Germany and the United Kingdom confirmed the same capability using cells from the testicles of humans. The extracted stem cells are known as human adult germline stem cells (GSCs)
Multipotent stem cells have also been derived from germ cells found in human testicles.
Dental pulp derived Stem Cells
Multipotent stem cells have been successfully recovered from dental pulp in the perivascular niche. Known as SHED cells (Stem cells Harvested from Exfoliated Deciduous teeth), they have been shown to have the same cellular markers and differential abilities of Mesenchymal Stem cells.
As deciduous baby teeth are shed naturally, this is a non invasive, painless way to harvest stem cells either for storage or future medical use.
Open questions in adult stem cell research
- How do adult stem cells arise? Are they residual embryonic stem cells? If so, what has stopped them differentiating: why are they still stem cells when most cells have differentiated?
- Are stem cells found in different tissues fundamentally distinct, or is there a universal adult stem cell? Stem cells derived from different adult tissue can have remarkably similar properties. Research on adult stem cells has revealed that they can be induced to produce cell types of a variety of tissues. Do some or all adult stem cells belong to a single lineage but behave differently depending on extracellular cues?
- Which adult tissues harbor stem cells? Do tissues that apparently contain no stem cells rely on other sources of new cells, or is it a matter of time until stem cells are identified there?
- What molecular factors enable stem cell plasticity? While a lot is known about the cellular qualities that accompany multi- and pluripotency, the molecular/genetic factors that determine these qualities remain unclear. Could knowledge of these mechanisms allow us to reverse the process of differentiation and restore embryonic stem cell properties in adult stem cells or even differentiated cells?
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