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.