An adult stem cell is thought to be an undifferentiated cell, found among differentiated cells in a tissue or organ that can
renew itself and can differentiate to yield some or all of the major
specialized cell types of the tissue or organ. The primary roles of adult stem cells in a living organism are to maintain and repair the tissue in which they are found. 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). Unlike embryonic stem cells, which
are defined by their origin (the inner cell mass of the blastocyst), the origin of adult stem cells in some mature tissues is still under investigation.
Research on adult stem cells has generated a great deal of
excitement. 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.
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 forms all the types of blood cells in the body. A second population, called bone marrow stromal stem cells, 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.
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 oligodenrocytes, which are non-neuronal cells, and neurons, or nerve cells.
A. Where are adult stem cells found, and what do they normally do?
Adult stem cells have been identified in many organs and tissues,
including brain, bone marrow, peripheral blood, blood vessels, skeletal
muscle, skin, teeth, heart, gut, liver, ovarian epithelium, and testis.
They are thought to reside in a specific area of each tissue (called a
"stem cell niche"). In many tissues, current evidence suggests that
some types of stem cells are pericytes, cells that compose the
outermost layer of small blood vessels. Stem cells may remain quiescent
(non-dividing) for long periods of time until they are activated by a
normal need for more cells to maintain tissues, or by disease or tissue
injury.
Typically, there is a very small number of stem cells in each
tissue, and once removed from the body, their capacity to divide is
limited, making generation of large quantities of stem cells difficult.
Scientists in many laboratories are trying to find better ways to grow
large quantities of adult stem cells in cell culture
and to manipulate them to generate specific cell types so they can be
used to treat injury or disease. Some examples of potential treatments
include regenerating bone using cells derived from bone marrow stroma,
developing insulin-producing cells for type 1 diabetes, and repairing
damaged heart muscle following a heart attack with cardiac muscle cells.
What tests are used for identifying adult stem cells?
Scientists often use one or more of the following methods to
identify adult stem cells: (1) label the cells in a living tissue with
molecular markers and then determine the specialized cell types they
generate; (2) remove the cells from a living animal, label them in cell
culture, and transplant them back into another animal to determine
whether the cells replace (or "repopulate") their tissue of origin.
Importantly, it must be demonstrated that a single adult stem cell
can generate a line of genetically identical cells that then gives rise
to all the appropriate differentiated cell types of the tissue. To
confirm experimentally that a putative adult stem cell is indeed a stem
cell, scientists tend to show either that the cell can give rise to
these genetically identical cells in culture, and/or that a purified
population of these candidate stem cells can repopulate or reform the
tissue after transplant into an animal.
Adult Stem Cells
As indicated above, scientists have reported that adult stem cells occur in many tissues and that they enter normal differentation pathways to form the specialized cell types of the tissue in which they reside.
Normal differentiation pathways of adult stem cells. In a
living animal, adult stem cells are available to divide, when needed,
and can give rise to mature cell types that have characteristic shapes
and specialized structures and functions of a particular tissue. The
following are examples of differentiation pathways of adult stem cells that have been demonstrated in vitro or in vivo.
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, and macrophages.
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 andoligodendrocytes.
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.
Transdifferentiation.A number of experiments have reported
that certain adult stem cell types can differentiate into cell types
seen in organs or tissues other than those expected from the cells'
predicted lineage (i.e., brain stem cells that differentiate into blood
cells or blood-forming cells that differentiate into cardiac muscle
cells, and so forth). This reported phenomenon is called
transdifferentiation. Although isolated instances of transdifferentiation have been
observed in some vertebrate species, whether this phenomenon actually
occurs in humans is under debate by the scientific community. Instead
of transdifferentiation, the observed instances may involve fusion of a
donor cell with a recipient cell. Another possibility is that
transplanted stem cells are secreting factors that encourage the
recipient's own stem cells to begin the repair process. Even when
transdifferentiation has been detected, only a very small percentage of
cells undergo the process.
In a variation of transdifferentiation experiments, scientists have
recently demonstrated that certain adult cell types can be
"reprogrammed" into other cell types in vivo using a well-controlled
process of genetic modification (see Section VI for a discussion of the
principles of reprogramming). This strategy may offer a way to
reprogram available cells into other cell types that have been lost or
damaged due to disease. For example, one recent experiment shows how
pancreatic beta cells, the insulin-producing cells that are lost or
damaged in diabetes, could possibly be created by reprogramming other
pancreatic cells. By "re-starting" expression of three critical
beta-cell genes in differentiated adult pancreatic exocrine cells,
researchers were able to create beta cell-like cells that can secrete
insulin. The reprogrammed cells were similar to beta cells in
appearance, size, and shape; expressed genes characteristic of beta
cells; and were able to partially restore blood sugar regulation in
mice whose own beta cells had been chemically destroyed. While not
transdifferentiation by definition, this method for reprogramming adult
cells may be used as a model for directly reprogramming other adult
cell types.
In addition to reprogramming cells to become a specific cell type, it
is now possible to reprogram adult somatic cells to become like
embryonic stem cells (induced pluropotent stem cells) through the introduction of embryonic genes. Thus, a source of cells
can be generated that are specific to the donor, thereby avoiding
issues of histocompatibility, if such cells were to be used for tissue
regeneration. However, like embryonic stem cells, determination of the
methods by which iPSCs can be completely and reproducibly committed to
appropriate cell lineages is still under investigation.
What are the key questions about adult stem cells?
Many important questions about adult stem cells remain to be answered. They include:
How many kinds of adult stem cells exist, and in which tissues do they exist?
How do adult stem cells evolve during development and how are they
maintained in the adult? Are they "leftover" embryonic stem cells, or
do they arise in some other way?
Why do stem cells remain in an undifferentiated state when all the
cells around them have differentiated? What are the characteristics of
their “niche” that controls their behavior?
Do adult stem cells have the capacity to transdifferentiate, and is it
possible to control this process to improve its reliability and
efficiency?
If the beneficial effect of adult stem cell transplantation is a
trophic effect, what are the mechanisms? Is donor cell-recipient cell
contact required, secretion of factors by the donor cell, or both?
What are the factors that control adult stem cell proliferation and differentiation?
What are the factors that stimulate stem cells to relocate to sites of
injury or damage, and how can this process be enhanced for better
healing?
Adult Stem Cells 
