TRANSPLANTATION AND EMBRYONIC STEM CELL RESEARCH: A CURE FOR DIABETES? 

Why transplant?

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 complications.

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 islet transplantation?

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 survival."

"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 hypoxia.

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 conditions.

Engineering a bioartificial pancreas

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 cell loading.

"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 cells?

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 system.

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 tissue type.