Stem Cells
During the
early stage
lopment the
blastocyst consists of very few cells. Any cell removed from the blastocyst has
the potential to differentiate into any type of adult cell if given the
appropriate signals. These cells are called totipotent. As the blastocyst develops,
cells communicate, become organised and begin to become specialised. Cells of
the embryoblast (see Chapter 11) are pluripotent and capable of differentiating
into any cell type of the three germ layers: ectoderm, mesoderm and endoderm.
After gastrulation cells of each germ layer are generally limited in their
differentiation capabilities to become cell types associated with that germ
layer (Figure 16.1).
The majority
of adult tissues are composed of terminally differentiated cells that are
mitotically stable. When they proliferate their daughter cells have the same
differentiated phenotype, that is, an adipocyte will divide to produce more
adipocytes. Some tissues have adult stem cell populations that contribute to
cellular replacement. These tissue‐specific stem cells are important in
replacing cells lost through normal bodily functions, such as keratinocytes
from the surface of the epidermis, epithelial cells lining the gastrointestinal
tract, red blood cells that have a limited life span and satellite cells in
skeletal muscle (Figure 16.2).
Stem cell
niches have been described in these tissues as local microenvironments with
interactions between stromal cells and stem cells that maintain and regulate
this progenitor population. Anatomically these niches are often very small and
maintain only a small number of stem cells through short‐range signalling
factors. Some daughter cells will fall outside the niche and differentiate, but
other daughter cells will remain within the niche and maintain the stem cell
population.
Some adult
stem cells have the potential to develop into a limited range of differentiated
cell types. A good example would be haematopoietic stem cells in adult bone
marrow that are described as multipotent and can differentiate into any type of
blood cell but cannot become cells of another tissue.
The usage of
the terms ‘progenitor’ and ‘stem cell’ often overlap, but a progenitor cell is
considered to be a cell that can produce cells of just one lineage, whereas an
adult stem cell is able to differentiate into a small range of different cell
types. The primary function of both is to replace lost cells, and they are
relatively inactive until required. Stem cells in the embryo form the complex
tissues of the body and create the different cell types involved, but adult
stem cells maintain those tissues.
Although
some tissues have stem cell populations able to main- tain and repair
themselves, other tissues are very poor at responding to injury. For example,
severed nerves leave structures without innervation, causing sensory loss or
muscular impairment. As nerves primarily consist of neuronal axons, damage
means much of the cell remains intact, but the axons no longer reach the target
structure and function is lost. There is no way for the axons to reattach themselves
and no way for the cell body to extend new axonal growths. Similarly the death
of neuronal cells in the brain, such as those of the substantia nigra in the
development of Parkinson’s disease, cannot be replaced by an existing stem cell
pool. The most common cause of vision loss is age‐related macular degeneration,
caused by damage to retinal pigment epithelium (RPE) cells that support the
photoreceptor cells of the macula. There is no natural source of stem cells here
to replace the lost cells. For each of these examples the introduction of stem
cells has been studied as potential treatments for these conditions. Stem cells
for use in regenerative medicine may be derived from the blastocyst or from
adult stem cell populations, and each source has its own advantages and
disadvantages. Many investigations into stem cell–based regenerative medicine
applications are still in the animal model phase.
The moral
dilemma of stem cell usage in medicine is based on a conflict between the
aspiration to alleviate pain and suffering and the duty to respect life. When
using embryonic stem cells these ethical values are in opposition. UK law
states that research can be carried out for certain purposes on embryos aged
between 1 and 14 days, and totipotent embryonic stem cells need to be taken
between 5 and 6 days to be useful in potential treatments (see Chapters 11 and
12). The 14 day barrier is identified as the point at which a zygote can no
longer divide to form twins, and the nervous system will not begin to develop
structurally until a week later (see Chapter 17). Should we regard the embryo,
before 14 days, as a person, or a potential person, with the rights by law
associated with that status? Many zygotes and blastocysts are lost naturally.
Some embryos are created for in vitro fertilisation (IVF) procedures but
are never allowed to continue to develop. Is that morally distinct from
creating embryos that will be destroyed specifically for research purposes? Or
for the medical treatment of others?
Many
researchers use ‘induced’ pluripotent stem cells (iPSCs) to combat difficult
ethical considerations they themselves might have. This involves the
dedifferentiation of a genetically modified adult cell, taking it backwards
through its developmental journey to a pluripotent stage (Figure 16.3). It is
currently unclear how these cells might differ from embryonic stem cells, and
because of the viral method used to create them they are not considered safe
for use in humans. If it becomes possible to create safe iPSCs from a patient’s
own cells, this method should avoid problems of allogeneic graft rejection.
The
potential uses of stem cells are continually being reviewed and supplemented,
and many patents have been submitted for a range of techniques. These have also
caused significant political and ethical debates.
Significant
hurdles remain, both ethically and biologically, but it seems clear that stem
cells will be an important resource for rstanding and treating many currently
incurable diseases and conditions.
