Chapter 067. Applications of Stem Cell Biology in Clinical Medicine (Part 3) pot

Chapter 067. Applications of Stem Cell
Biology in Clinical Medicine
(Part 3)

Diabetes Mellitus
The success of islet cell and pancreas transplantation provides proof of
concept for a cell-based approach for type I diabetes. However, the demand for
donor pancreata far exceeds the number available, and maintenance of long-term
graft survival remains a problem. The search for a renewable source of stem cells
capable of regenerating pancreatic islets has therefore been intensive.
Pancreatic βcell turnover occurs in the normal pancreas, although the
source of the new βcells is controversial. Attempts to promote endogenous
regenerative processes have not yet been successful, but this remains a potentially
viable approach. A number of different cell types are candidates for use in stem
cell replacement, including ES cells, hepatic progenitor cells, pancreatic ductal
progenitor cells, and bone marrow stem cells. Successful therapy will depend on
developing a source of cells that can be amplified and have the ability to
synthesize, store, and release insulin when it is required, primarily in response to
changes in the glucose level. The proliferative capacity of the replacement cells
must be tightly regulated to avoid excessive expansion of βcell numbers with the
consequent development of hyperinsulinemia/hypoglycemia, and the cells must
avoid immune rejection. Although ES cells can be differentiated into cells that
produce insulin, these cells have relatively low insulin content and a high rate of
apoptosis, and they generally lack the capacity to normalize blood glucose in
diabetic animals. Thus, ES cells have not yet been useful for the large-scale
production of differentiated islet cells.
During embryogenesis, the pancreas, liver, and gastrointestinal tract are all
derived from the anterior endoderm, and transdifferentiation of the pancreas to
liver and vice versa has been observed in certain pathologic conditions.
Multipotential stem cells also reside within gastric glands and intestinal crypts.
Thus, hepatic, pancreatic, and/or gastrointestinal precursor cells may be candidates

for cell-based therapy of diabetes.
Nervous System
Neural cells have been differentiated from a variety of stem cell
populations. Human ES cells can be induced to generate neural stem cells, and
these cells can give rise to neurons, oligodendroglia, and astrocytes. These neural
stem cells have been transplanted into the rodent brain with formation of
appropriate cell types and no tumor formation. Multipotent stem cells present in
the adult brain can also generate all of the major neural cell types, but highly
invasive procedures would be necessary to obtain autologous cells. Fetal neural
stem cells derived from miscarriages or abortuses are an alternative, and a clinical
trial of fetal neural stem cells in Batten disease is commencing.
Transdifferentiation of bone marrow and adipose stem cells into neural stem cells,
and vice versa, has been reported, and clinical trials of such cells have begun for a
number of neurologic disorders. Clinical trials of a conditionally immortalized
human cell line and of human umbilical cord blood cells in stroke are also
planned. Neurologic disorders that have already been targeted for stem cell
therapies include spinal cord injury, amyotrophic lateral sclerosis, stroke,
traumatic brain injury, Batten disease, and Parkinson's disease. In Parkinson's
disease, the major motor features result from the loss of a single cell population,
dopaminergic neurons within the substantia nigra pars compacta. Two clinical
trials of fetal nigral transplantation failed to meet their primary endpoint and were
complicated by the development of dyskinesia. Transplantation of stem cell–
derived dopamine-producing cells offers a number of potential advantages over
fetal transplants, including the ability of stem cells to migrate and disperse within
tissue, the potential for engineering regulatable release of dopamine, and the
ability to engineer cells to produce factors that will enhance cell survival.
Nevertheless, the experience with fetal transplants points out the difficulties that
may be encountered.
At least some of the neurologic dysfunction after spinal cord injury reflects
demyelination, and both ES cells and marrow-derived stem cells are able to

facilitate remyelination after experimental spinal cord injury. Clinical trials of
marrow-derived stem cells have already begun, and this may be the first disease
targeted for the clinical use of ES cells. Marrow-derived stem cells are also being
used in the treatment of stroke, traumatic brain injury, and amyotrophic lateral
sclerosis (ALS), where possible benefits are more likely to be indirect trophic
effects or remyelination rather than neuron replacement. At present, no population
of transplanted stem cells has been shown to generate neurons that extend axons
over long distances to form synaptic connections (such as would be necessary for
replacement of upper motor neurons in ALS, stroke, or other disorders).
Liver
Transplantation is currently the only successful treatment for end-stage
liver diseases, but this approach is limited by the shortage of liver grafts. Clinical
trials of hepatocyte transplantation demonstrate that it can potentially substitute for
organ transplantation, but the paucity of available cells also limits this strategy.
Potential sources of stem cells include endogenous liver stem cells (such as oval
cells), ES cells, bone marrow cells, and umbilical cord blood cells. Although a
series of studies in humans as well as animals suggested that transplanted bone
marrow stem cells can generate hepatocytes, this phenomenon largely reflects the
fusion of the transplanted cells with endogenous liver cells, giving the erroneous
appearance of new hepatocytes. ES cells have been differentiated into hepatocytes
and transplanted in animal models of liver failure without formation of teratomas.