Xunlei Zhou, PhD and Peter Gruss, PhD,
Max Planck Institute of Biophysical Chemistry, Göttingen
Klinik
& Forschung 2002; 8(2):51-52
Insulin-dependent
(type1) diabetes is a widespread chronic disease affecting every age group. The
symptoms can at least partially be treated by routine injections of insulin;
even so, e.g. vascular complications are common and often a cause of early death.
“Curing” the disease would ideally involve a permanent replacement of the
beta-cell mass of the patients. Today, the sole sources are human pancreatea or
islets of Langerhans. This obviously restricts the large-scale application of
this therapy. Recently, progress in the field of stem cell biology opened new
possibilities to generate large amounts of functional pancreatic endocrine cells
in vitro, which could eventually be used for transplantation.
Embryonic
stem cells
Stem cells have the potential to
generate many types of differentiated cells. Since every tissue of the organism
(be it skin, brain, muscle, pancreas or any other) will eventually be formed
from the embryonic stem cells (ESC, the cells of the early embryo). These are
the ultimate “stem cells”, which possess the ability to generate any kind of
tissue. Stem cells of several species, including mouse and human, have been
cultivated in vitro, passaged in culture and kept as “cell lines”
which then can be maintained and grown circumventing the need of a permanent
embryo supply. Outside their natural environment, ESC do not form an embryo but
differentiate in a seemingly random manner into neurons, muscle cells,
epithelial cells, etc. It has been demonstrated that they can also spontaneously
become insulin-producing cells (see e.g.1).
Moreover, ESC-derived insulin-producing cells have been shown to correct
experimentally induced diabetes in mice 2.
Now, in order to obtain reliable large numbers of these cells (for
transplantation purposes), we have to be able to “guide” the ESC along the
desired differentiating pathway (rather than relying on the unpredictable
occurrence of insulin-producing cells in ESC culture dishes). Recently, Lumelsky
and coworkers 3
have been able to coax mouse ESC into producing the types of cells, which
express insulin and other pancreatic endocrine hormones. Moreover, the cells
were able to assemble in culture and form clusters similar to normal pancreatic
islets from every point of view. These in vitro-generated islets respond to
glucose by secreting insulin, and, after being injected into diabetic mice, they
receive vascularization and maintain their islet shape.
Pancreatic
stem cells
A second source of stem cells is the pancreas itself. Pancreatic stem
cells when compared to ESC have the advantage of being already primed to
specifically produce pancreatic cell types. The endocrine cells of the rat
pancreatic islets turn over every 40-50 days through the parallel processes of
cell death (apoptosis) and cell proliferation (and differentiation). At least
some of the new cells are born from progenitor epithelial cells in the
pancreatic ducts 4.
An intermediate filament protein called nestin has been identified
as a marker for multipotent stem cells in the central nervous system.
Nestin-expressing cells have also been found in the pancreatic islet, suggesting
that not only the ductal cells, but also some islet cells could have stem cell
properties 5. This hypothesis is
supported by the fact that the administration of islet trophic factors (e. g.
glucose) to rats results in an increase of islet cell mass, which suggests that
islet progenitor cells exist within the islets 4.
Nestin-positive
islet cells can be isolated and grown in culture for several months, where they
show ample proliferation and multipotential capacities 4. At least one additional group of
potential pancreatic stem cells, expressing ngn3, has been described. The
relation between these cells and the nestin-expressing cells is still unknown4.
Finally, exocrine pancreatic cells have been shown to become endocrine
cells by going through a process of dedifferentiation that would transform them
into stem cells 6.
Reasonable amounts of human ductal cells can be obtained by cultivating
pancreatic tissue under certain conditions. Moreover, human islets have been
grown in vitro for more than one year. Under these conditions, islet cells are
able to transdifferentiate into exocrine cells and also undifferentiated
cells. The latter are presumably pancreatic stem cells 7,8.
These developments open the possibility of treating patients with
“their own” islet cells, grown ex vivo from his/her own pancreas, then
transplanted back. The concept has already been proven in the mouse model.
Ramiya and coworkers have grown pancreatic ductal cells isolated from
prediabetic adult non-obese diabetic mice, then induced them to produce
functioning islets containing alpha, beta and delta cells. These islets were
able to overcome the symptoms of insulin-dependent diabetes after being
implanted into non-obese diabetic mice9.
Transcriptional
complexity
Paradoxically, these cells which are attracting so much attention and
inspiring so much hope are not very well understood at the molecular level.
Detailed knowledge of the transcriptional control of the differentiated state
would open a new door to therapy, namely the possibility to jump-start islet
neogenesis at will by introducing appropriate regulator genes (or proteins) into
the stem cells naturally present in the pancreas of patients.
Current
research favors a complex network of regulation involving key players like Pdx1,
Ngn3, NeuroD, Pax4 and Pax6 as responsible for pancreatic endocrine
differentiation. Members of the Notch family of transcriptional activators would
contribute to regulating the balance between differentiation and proliferation 10,11,1213,14,15,16.
The therapeutic prospects opened by this approach are tantalizingly underlined
by recent results showing that ectopic expression of Ngn3 is sufficient to turn
endodermal cells into endocrine cells able to form islets expressing glucagon
and somatostatin 17.
Dietary
modification
Also enticing are reports suggesting
that pancreatic stem cells can be coaxed into producing new endocrine cells by
dietary means. For instance, copper deprivation contributes to the neogenesis of
alpha and beta cells in the pancreatic ducts 18, and hydrolyzed
casein promotes islet neogenesis at least in certain strains of rat 19. Finding a way to exploit the relation between diet and pancreatic
endocrine cells opens intriguing possibilities to therapy.
Stem
cells and cancer
Finally, one more reason to study pancreatic stem cells is cancer
research. Pancreatic cancer is very aggressive and difficult to treat, and is
among the leading causes of death. It is very likely that most pancreatic cancer
originates in stem cells. Insight into the molecular mechanisms of their
proliferative and differentiative abilities could bring great rewards also in
this area 20,21,22.
References
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