TRANSPLANTATION AND EMBRYONIC
STEM CELL RESEARCH: A CURE FOR DIABETES?
Early attempts at islet cell transplantation
to treat diabetes date to the nineteenth century, decades before
the discovery of insulin in the 1930s. In recent years, research
has focused on the anatomical sites best suited for hosting
transplanted islet cells. Experimental sites have included the
spleen, liver, peritoneal cavity, omentum, subcutaneous tissues
and gastric submucosa. However, many transplant attempts at a
variety of anatomical sites have failed because of a variety of
While transplanting islet cells into the liver is current
practice, improvements in biomedical devices have improved the
overall success rates of islet transplantation. Recent advances
in islet transplantation are discussed in the January issue of
Cell Transplantation (Vol. 17 No.9).
Which anatomical sites are best for
A review evaluating both anatomical site choice for islet cell
transplantation and an ideal source of islet cells was the focus
of a report by Dr. Dirk Van der Windt and colleagues at the
Thomas E. Starzl Transplantation Institute at the University of
Pittsburgh Medical Center. They concluded that transplantation
into the liver "may not provide the conditions favoring optimum
"Islet transplantation into the portal vein is current clinical
practice," said Van der Windt. "However, this site has several
characteristics that can hamper islet engraftment and survival."
According to Van der Windt, low oxygen tension and immune and
inflammatory responses are among factors that can account for
islet cell loss soon after transplantation. Thus, alternative
anatomical sites for islet transplantation, sites offering
maximum engraftment potential, the efficacious use of insulin
and patient safety, are needed.
"The most physiological - and therefore perhaps most supportive,
microenvironment for islets - is the pancreas itself," said Van
der Windt and co-authors.
They also speculate on the value of porcine islet cells for
transplantation, suggesting that these cells offer greater
opportunities for selecting a donor at an age when the islets
have favorable properties, when islet-like cell clusters
isolated from fetal or neonatal piglets retain the ability to
mature and proliferate. In addition, these cells are believed to
be less immunogenic than adult islet cells and more resistant to
Van der Windt and colleagues suggest that porcine islet cells
can provide an unlimited source of islets and in quantities that
may satisfy the metabolic requirements of diabetic patients.
Too, they are able to produce insulin that both functions in
humans and offers opportunities for genetic modification that
may help overcome some of the unfavorable site-specific
Another review by Dr. Cherie Stabler and colleagues from the
Diabetes Research Institute and the Department of Biomedical
Engineering at the University of Miami (Florida), evaluated the
engineering of bio-hybrid devices and encapsulation technologies
that may aid in the success of islet transplants. According to
the researchers, the transplantation of islet cells into the
portal vein of the liver has presented several challenges.
Overcoming those challenges means recognizing important issues
such as vascularization, mechanical protection, device design,
biomaterial selection and quality control in device engineering.
"A recent focus has been to redesign bio-hybrid devices that
promote vascularization and effective nutrient delivery to
prevent islet cell necrosis and at the same time minimize device
volumes," said Stabler.
According to Stabler, one bio-hybrid design has been fabricated
for pre-vascularization to afford maximum nutrient delivery and
minimal exposure to inflammatory agents. At the same time,
macrodevices, such as hollow fibers, have also been used for
"The combination of these two treatments increased
vascularization and blood flow around the bioartificial pancreas
when compared to control implants," noted Stabler.
Encapsulation is also a technique for minimizing both immune
response and the need for high dose immunosuppressive protocols.
By coating the surface of the cell with semi-permeable
biomaterial, the ability of host cells to recognize surface
antigens on implanted cells is impaired and provides a barrier
between the host and transplanted cells. Masking immune
recognition also opens the possibility for xenotransplantation.
"Biomaterials used for encapsulation should be
well-characterized, pharmaceutical grade and verified as pyrogen
and endotoxin-free," explained Stabler. "It is critical to
establish guidelines for generating capsules optimized for
biocompatibility, immunoprotection and islet function."
Researchers supported the use of the portal vein as a site for
islet transplantation, but noted that there are issues with
injecting encapsulated cells into the liver. Finally, the
research team suggested decreasing capsule size to nano-scale
and combining PEGylation coating of capsules with a layer of
poly(ethylene) glycol molecules with low-dose immunosuppression
to improve engraftment and long-term function.
What about stem
Human embryonic stem cells emerge five to
seven days into an embryo's development, when the embryo is a
hollow sphere. The sphere consists of an outer layer of cells
that goes on to form the placenta, and an inner cluster of cells
known as the inner cell mass that goes on to form all of the
tissues of the body. At this stage, the embryo is known as a blastocyst. Embryonic stem cells arise from the inner cell mass.
(Picture shows a five-day-old embryo, known as a blastocyst. The
dark patch inside the blastocyst is the inner cell mass, from
which embryonic stem cells are obtained.) They have the
potential to differentiate, or specialize, into each of the 200
types of tissue in the body.
Researchers in numerous laboratories have
succeeded in obtaining human embryonic stem cells from embryos
in the petri dish. On their own in the petri dish, these cells
can differentiate spontaneously into specialized cells, such as
beating heart cells. By exposing them to growth factors,
scientists have succeeded in prompting the cells to
differentiate in the petri dish into nerve cells, pancreatic
cells and cardiac cells. Scientists' hope is that such
specialized cells could then be transplanted into patients to
treat a host of disorders, including Alzheimer's disease,
Parkinson's disease, diabetes, heart disease, stroke and spinal
cord injuries. However, researchers have much to learn about how
to grow and maintain such differentiated cells at a stage in
their development that would make them useful for
transplantation into patients.
But embryonic stem cells still have
disadvantages. First, transplanted cells sometimes grow into
tumours. Second, the human embryonic stem cells that are
available for research would be rejected by a patient's immune
Tissue-matched transplants could be made by either creating a
bank of stem cells from more human embryos, or by 'cloning' a
patient's DNA into exisiting stem cells to customize them. This
is laborious and ethically contentious.
These problems could be overcome by using adult stem cells,
taken from a patient, that are treated to repair problems and
then put back. But until now some researchers were not convinced
that adult stem cells could, like embryonic ones, make every
Copyright of Lee Chung Horn
Diabetes & Endocrinology 2009