For many years, researchers have been seeking to
understand the body’s ability to repair and replace
the cells and tissues of some organs, but not others.
After years of work pursuing the how and why of
seemingly indiscriminant cell repair mechanisms,
scientists have now focused their attention on adult
stem cells. It has long been known that stem cells
are capable of renewing themselves and that they
can generate multiple cell types. Today, there is new
evidence that stem cells are present in far more
tissues and organs than once thought and that these
cells are capable of developing into more kinds of
cells than previously imagined. Efforts are now
underway to harness stem cells and to take
advantage of this new found capability, with the goal
of devising new and moreeffective treatments for a
host of diseases and disabilities. What lies ahead for
the use of adult stem cells is unknown, but it is
certain that there are many research questions to be
answered and that these answers hold great promise
for the future.
WHAT IS AN ADULT STEM CELL?
Adult stem cells, like all stem 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. Typically, stem cells generate
an intermediate cell type or types before they
achieve their fully differentiated state. The intermediate
cell is called a precursor or progenitor cell.
Progenitor or precursor cells in fetal or adult tissues are
partly differentiated cells that divide and give rise to
differentiated cells. Such cells are usually regarded as
“committed” to differentiating along a particular
cellular development pathway, although this
characteristic may not be as definitive as once
thought [82] (see Figure 4.1. Distinguishing Features of
Progenitor/Precursor Cells and Stem Cells).
Adult stem cells are rare. Their primary functions are
to maintain the steady state functioning of a cell—
called homeostasis—and, with limitations, to replace
cells that die because of injury or disease [44, 58].
For example, only an estimated 1 in 10,000 to 15,000
cells in the bone marrow is a hematopoietic (bloodforming)
stem cell (HSC) [105]. Furthermore, adult
stem cells are dispersed in tissues throughout the
mature animal and behave very differently,
depending on their local environment. For example,
HSCs are constantly being generated in the bone
marrow where they differentiate into mature types of
blood cells. Indeed, the primary role of HSCs is to
replace blood cells [26] (see Chapter 5. Hematopoietic
Stem Cells). In contrast, stem cells in the small
intestine are stationary, and are physically separated
from the mature cell types they generate. Gut epithelial
stem cells (or precursors) occur at the bases of
crypts—deep invaginations between the mature,
differentiated epithelial cells that line the lumen of the
intestine. These epithelial crypt cells divide fairly often,
but remain part of the stationary group of cells they
generate [93].
Unlike embryonic stem cells, which are defined by
their origin (the inner cell mass of the blastocyst),
adult stem cells share no such definitive means of
characterization. In fact, no one knows the origin of
adult stem cells in any mature tissue. Some have
proposed that stem cells are somehow set aside
during fetal development and restrained from
differentiating. Definitions of adult stem cells vary in
the scientific literature range from a simple description
of the cells to a rigorous set of experimental
criteria that must be met before characterizing a
particular cell as an adult stem cell. Most of the information
about adult stem cells comes from studies of
mice. The list of adult tissues reported to contain stem
cells is growing and includes bone marrow, peripheral
blood, brain, spinal cord, dental pulp, blood vessels,
skeletal muscle, epithelia of the skin and digestive
system, cornea, retina, liver, and pancreas.
In order to be classified as an adult stem cell, the cell
should be capable of self-renewal for the lifetime of
the organism. This criterion, although fundamental to
the nature of a stem cell, is difficult to prove in vivo. It
is nearly impossible, in an organism as complex as a
human, to design an experiment that will allow the
fate of candidate adult stem cells to be identified in
vivo and tracked over an individual’s entire lifetime.
Ideally, adult stem cells should also be clonogenic. In
other words, a single adult stem cell should be able
to generate a line of genetically identical cells, which
then gives rise to all the appropriate, differentiated
cell types of the tissue in which it resides. Again, this
property is difficult to demonstrate in vivo; in practice,
scientists show either that a stem cell is clonogenic in
vitro, or that a purified population of candidate stem
cells can repopulate the tissue.
An adult stem cell should also be able to give rise to
fully differentiated cells that have mature phenotypes,
are fully integrated into the tissue, and are capable
of specialized functions that are appropriate for the
tissue. The term phenotype refers to all the observable
characteristics of a cell (or organism); its shape
(morphology); interactions with other cells and the
non-cellular environment (also called the extracellular
matrix); proteins that appear on the cell surface
(surface markers); and the cell’s behavior (e.g.,
secretion, contraction, synaptic transmission).
The majority of researchers who lay claim to having
identified adult stem cells rely on two of these characteristics
—appropriate cell morphology, and the
demonstration that the resulting, differentiated cell
types display surface markers that identify them as
belonging to the tissue. Some studies demonstrate
that the differentiated cells that are derived from
adult stem cells are truly functional, and a few studies
show that cells are integrated into the differentiated
tissue in vivo and that they interact appropriately with
neighboring cells. At present, there is, however, a
paucity of research, with a few notable exceptions, in
which researchers were able to conduct studies of
genetically identical (clonal) stem cells. In order to
fully characterize the regenerating and self-renewal
capabilities of the adult stem cell, and therefore to
truly harness its potential, it will be important to
demonstrate that a single adult stem cell can,
indeed, generate a line of genetically identical cells,
which then gives rise to all the appropriate, differentiated
cell types of the tissue in which it resides.
EVIDENCE FOR THE PRESENCE OF
ADULT STEM CELLS
Adult stem cells have been identified in many animal
and human tissues. In general, three methods are
used to determine whether candidate adult stem
cells give rise to specialized cells. Adult stem cells
can be labeled in vivo and then they can be
tracked. Candidate adult stem cells can also be
isolated and labeled and then transplanted back into
the organism to determine what becomes of them.
Finally, candidate adult stem cells can be isolated,
grown in vitro and manipulated, by adding growth
factors or introducing genes that help determine
what differentiated cells types they will yield. For
example, currently, scientists believe that stem cells in
the fetal and adult brain divide and give rise to more
stem cells or to several types of precursor cells, which
give rise to nerve cells (neurons), of which there are
many types. It is often difficult—if notimpossible—to distinguish adult, tissue-specific stem cells from progenitor cells, which are found in fetal or adult tissues and are partly differentiated cells that divide and give rise to differentiated cells. These are cells found in many organs that are generally thought to be present to replace cells and maintain the integrity of the tissue. Progenitor cells give rise to certain types of cells— such as the blood cells known as T lymphocytes, B lymphocytes, and natural killer cells—but are not thought to be capable of developing into all the cell types of a tissue and as such are not truly stem cells. The current wave of excitement over the existence of stem cells in many adult tissues is perhaps fueling claims that progenitor or precursor cells in those tissues are instead stem cells. Thus, there are reports of endothelial progenitor cells, skeletal muscle stem cells, epithelial precursors in the skin and digestive  system, as well as some reports of progenitors or stem cells in the pancreas and liver.