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Regenerative concepts for the therapy of metabolic diseases

Prof. Dr. Alfred Königsrainer, Medical Director of the Department of General, Visceral and Transplantation Surgery in Tübingen (Photo: Department of General, Visceral and Transplantation Surgery at UKT)

Prof. Dr. Alfred Königsrainer, Medical Director of the Department of General, Visceral and Transplantation Surgery in Tübingen (Photo: Department of General, Visceral and Transplantation Surgery at UKT)

At the Department of General, Visceral and Transplantation Surgery at the University Hospital of Tübingen, the topic of regeneration relates to islets of Langerhans transplantation and liver replacement. The research is relevant to numerous different projects.

Six years ago, Dr. Nicolas Lembert established the experimental islet cell laboratory at the University Hospital in Tübingen (UKT). In cooperation with the Centre for Clinical Transfusion Medicine (ZKT), Lembert then further developed the laboratory into a cleanroom laboratory which is the only one in Germany authorised to produce cells of the islets of Langerhans found in the human pancreas. The cells are transplanted into type 1 diabetes patients in order to restore the patient’s own insulin production.

The current approach involves the injection of donor islet cells into the portal vein of the liver. "This process leads to the settlement of the islet cells in the liver. However, over the next five years, the cells steadily lose their function and insulin production decreases," said Lembert, who regards the transport of the islet cells by way of the blood circulation as the critical point in the process. "Up to 50 per cent of all islet cells are destroyed in the blood, mainly caused by coagulation and immune reactions."

Looking for a suitable substitute home for islets of Langerhans

In order to avoid these problems, Lembert and his team are looking for other possibilities to introduce the islet cells into the body. Lembert has received great support from Prof. Dr. Alfred Königsrainer, the Medical Director of the Hospital. "When islets were transplanted into the liver for the first time approximately five years ago, the excitement was enormous. However, what we see now is very demotivating. Nevertheless, we just have to continue our work," said Königsrainer.

Lembert and his team of researchers have identified the intestinal wall as a potential site for islets of Langerhans transplants. The team is currently testing different possibilities to grow the islets on the intestinal wall. It is possible to inject the cells below the intestinal mucosa. "For example, although the intestinal wall protects the islets cells from coming into direct contact with the blood, the islets are, nevertheless, well supplied with oxygen and nutrients through the intestinal blood circulation. In addition, the size of the intestinal wall provides ample space for the transplants. Equally important for us is that the islet cell preparations do not need to be as pure in comparison with the cell preparations injected via the portal vein into the liver. Certain exocrine contaminations are tolerated," explained Lembert.

Lembert is currently preparing a research project in which the new transplantation method will be tested in an animal model. In this project, Lembert’s group is cooperating with the RadiologicalHospital of the UKT. Using magnetic resonance imaging (MRI), the radiologists hope to follow the path of iron-particle-labelled islet cells. "The methods used to prepare the cells and for transplantation have been established," said Lembert who believes that the first experiments will be undertaken in 2007.

Problems with the provision of organs

The researchers often face problems when they decide to work with human islet cells. "The use of cells for transplants is generally widely accepted; however, the use of the cells for research purposes, which always has to precede clinical application, is less acceptable to some people. In addition, the situation is made even more difficult because the cells have to be removed immediately after death," said Königsrainer.

The delivered material is always meticulously tested for its suitability for transplantation. "We have taken quality control to a very high standard and this is essential," said Lembert. Nevertheless, not all organs can be used for transplantation. If a donor organ does not comply with the qualities required for islet cell transplantation, or if there are insufficient cells for the recipient, transplantation is out of question. Only when the donor has given consent for the use of the cells for experimental purposes, can these cells be used for research.

Cell cultures with or without stem cells can help overcome shortages

Methods improving the proliferation of cells might, in future, help reduce shortages in supply. Lembert and his group are working on the proliferation of cells prior to transplantation. "We hope to use biomaterials as carriers, which form a stimulating matrix. An increase in cell numbers by a factor of between two and five would be excellent and I strongly believe that we will be able to achieve this," said Lembert optimistically. He is currently looking for an industrial partner with whom he could work together on this project. Another approach focuses on obtaining insulin-producing ß-cells that are usually isolated along with the islets of Langerhans.

Dr. Nicolas Lembert preparing island cells in the cleanroom laboratory. (Photo: Department of General, Visceral and Transplantation Surgery at UKT)

Dr. Nicolas Lembert preparing island cells in the cleanroom laboratory. (Photo: Department of General, Visceral and Transplantation Surgery at UKT)

Acute liver failure: Replacement system outside of the body can help

Königsrainer’s group of researchers are also focusing on the interaction of biomaterials and cellular components. "Led by Dr. Martin Schenk, some researchers are working on a bioartificial liver replacement system for clinical application. The researchers are supported in their work by researchers from the Institute of Anatomy at the University of Tübingen. In cooperation with the Department of Tissue Engineeringi, led by Prof. Dr. Thomas Skutella, the researchers have developed a liver reactor that represents an important model on the researchers’ road to developing liver replacements. The reactor is made up of individual modules that are cultivated with hepatocytes (liver cells).

"We are trying to establish liver dialysis systems, which would be of great importance in the detoxification of the blood in patients suffering acute liver failure," said Königsrainer. Until now, people who suffer from acute liver failure have to undergo liver transplantation; however, transplants are usually not available in sufficient numbers nor at the speed with which they are required. The scientists from Tübingen are working together with Hechingen-based GAMBRO Dialysatoren GmbH, to develop the bioartificial liver substitute into a dialysis system that would take over the functions of the liver reliably, outside of the body. This would give the patient’s liver time to regenerate and bridge the waiting time until transplantation.

Stem cell therapy for the regeneration of sphincters

Königsrainer relies on the broad skills of the Anatomical Institute when working on the development of regenerative medical products. In cooperation with Skutella, Königsrainer is developing a concept involving the use of muscle-derived stem cells for the treatment of reflux disease. "We are working on the regeneration of the sphincter of the oesophagus by injecting stem or precursor cells," said Königsrainer who is also looking for an industrial partner for this project.

leh - 20.08.06
© BIOPRO Baden-Württemberg GmbH, first published at www.bio-pro.de<, them Biotech/Life Sciences Portal of the State of Baden-Württemberg. All rights reserved.

Further information:

University Hospital of Tübingen
Department of General, Visceral and Transplantation Surgery

Prof. Dr. Alfred Königsrainer (Medical Director)
Phone: +49 (0)7071 29-86620
alfred [dot] koenigsrainer [at] med [dot] uni-tuebingen [dot] de

PD Dr. Nicolas Lembert (Head of Islet Cell Laboratory)
Phone: +49 (0)7071 29-87326
nicolas [dot] lembert [at] uni-tuebingen [dot] de

Dr. Martin Schenk (Head of Tissue Engineering/Liver Replacement)
Phone: +49 (0)7071 29-80397
martin.schenk@uni-tuebingen

Hoppe-Seyler-Straße 3
72076 Tübingen
Fax: 07071 29-5588
www.medizin.uni-tuebingen.de/allgemeine-chirurgie/<