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Thrombocytes and vessels – variable relations

It is possible to repair damaged cardiovascular system vessels with external stem and progenitor cells if they remain at the desired location. Thrombocytes have a key role in the process known as "homing".

Cardiovascular diseases are the number one cause of death in Western industrial countries, in Europe one in two people die from cardiovascular disease. For several years the field of regenerative medicine has been developing promising approaches for the research and treatment of cardiovascular diseases. Prof. Dr. Gawaz is the medical director of the Department of Cardiology and Vascular Diseases at the University Hospital in Tübingen (Internal Medicine III). He is involved in several projects focusing on the development of new therapies on the basis of stem cells and progenitor cells.

"In the last few years, controlled clinical studies have shown that therapy with autologousi stem cells has a favourable effect on the recovery of heart muscle tissue following an infarction. A major aspect of this new type of cell therapy is the effective enrichment of progenitor cells in the target tissue in order to regenerate myocardial tissue for example," said Gawaz addressing one of the major problems of cell therapy worldwide. The majority of progenitor cells introduced unfortunately do not remain in the target tissue. "Currently, only three to five percent of the progenitor cells remain in the myocardium, the rest migrates into the spleen, the liver and into the spinal marrow," said Gawaz. The researchers hope to be able to reduce this migration rate and have decided to examine the mechanisms of cell accumulation in the target tissue, a process known as "homing".

Clarification of the mechanisms of re-endothelialisation

It is known that thrombocytes have a major effect on the "homing" of stem and progenitor cells. Focusing on peripheral vessels, Gawaz and his colleagues are investigating the thrombocytic effect on the adhesion or migration of the cells in vitroi and in the animal model. In a large research project, the scientists are investigating the chemotactic, adhesive and migratory factors. This project is supported with funds provided by the University of Tübingen, the German Research Foundation and funds provided by foundations such as the Karl and Lore Stein Foundation, the Kuhn Foundation, the Wilhelm Sander Foundation and the Novartis Foundation.

Intravital microscopy and two-photon microscopy (Figure: UKT)

Intravital microscopy and two-photon microscopy (Figure: UKT)

Within the last two years, the research group from Tübingen has succeeded in setting up an in vitro technology and in vivoi animal models as the basis for analysing the process of "homing". "The major obstacle was the visualisation under dynamic conditions," said Gawaz who, with his team, finally managed to adapt two microscopic methods for this purpose. Using two-photon microscopy and intravital microscopy, the group of researchers is now able to analyse the "homing" processes without having to remove vessels.

Tissue regeneration (Figure: UKT)

Tissue regeneration (Figure: UKT)

The researchers observed different adhesion mechanisms for different target sites and will now have to identify those adhesion molecules that enhance the "homing" process. "Adhesion molecules are essential in the control of stem cell attachment in the target tissue. We want to use intelligent recombinant bifunctional molecules to modulate the target tissue in order to affect and enhance "homing"," said Gawaz explaining the next steps in their research. In future, it might eventually be possible to prophylactically treat risk patients with such bifunctional molecules and facilitate the body’s own cell-based tissue regeneration.

Functional examinations on, and with, thrombocytes

There is also a second research project dealing with adhesion. This project is funded by the DFG. During his time as professor at the TU Munich, Gawaz was one of the founders of the biotechnology company ProCorde. This start-up company has developed the SIGSCREEN platform which enables the in vitro production of progenitor cells from thrombocytes.


Cultivation of CD thrombocytes from CD34+ progenitor cells. Megakaryocytes were cultivated from CD34+ progenitor cells (left) and differentiated into thrombocytes (right). The electron microscope images show megakaryocytes (left) shedding thrombocytes which can then be “harvested” (right). After the adenoviral infection of these cells with a GFP construct, up to 40% GFP-positive CD thrombocytes can be differentiated after several culturing steps. (Figure: UKT)

The research cooperation has continued after the successful merger of the company with the English Trigen Holding AG, and Gawaz is looking for innovative antithrombotic substances based on the thrombocytes originally produced in Munich. Traditional substances such as aspirin are only able to affect aggregation. However, Gawaz wants to inhibit the secretion of thrombocytes and modulate adhesion. He believes that actual inhibition will have considerably more effective therapeutic options.

Thrombocytes are involved in the development of atherosclerosis. For example, many diabetics suffer from this disease and "represent a high-risk population for accelerated atherosclerosis," said Gawaz. He hopes to find out how thrombocytes or progenitor cells of healthy people differ from those of diabetics. In diabetics, progenitor cells often lead to "foam cells" (early atherogenetic cells) which have a decisive effect on plaque formation. "Scavenger receptors seem to have a decisive effect on the generation of foam cells. We are currently looking at the details of this process," said Gawaz. He believes that the scavenger receptors might be potential target structures of anti-atherosclerosis drugs.

Impaired progenitor cell functions in diseases and potential therapies (Figure: Hill et al., NEJM; Urbich et al., Kidney Int.)

Impaired progenitor cell functions in diseases and potential therapies (Figure: Hill et al., NEJM; Urbich et al., Kidney Int.)

Stem and progenitor cells represent the regenerative future

The ambitious and partially completed projects of the Tübingen scientists raise hope for an early and broad implementation of the results in clinical application. Cell therapy has promising potential: "For many patients suffering from myocardial infarctions, regenerative therapies might, within the not too distant future, become a standard therapy," said Gawaz and added: "The methods are being validated and acceptance is growing. The health insurance companies also support interventions undertaken to treat acute myocardial infarctions." Gawaz is very optimistic: "In the long term, it might be possible to treat all patients with a certain risk potential in specific therapy centres and it will at some stage most likely also be possible on an outpatient basis."

In order to further promote regenerative medicine, Gawaz is backing the efforts to support new ideas and establish network structures: "The Centre for Regenerative Medicine at the University of Tübingen offers great opportunities. We will be able to validate certain questions in own studies and offer everything from drug discovery to the development of therapies. This will help us become unbeatable and place us well ahead of the pharmaceutical industry." Gawaz hopes that risk research such as that which has been undertaken by the company ProCorde with the support of the Bavarian state and venture capital investors will be further promoted and supported in the Tübingen region.

leh - 20.10.2006
© BIOPRO Baden-Württemberg GmbH, first published at www.bio-pro.de<, the Biotech/Life Sciences Portal of the State of Baden-Württemberg. All rights reserved.

Further information:

University Hospital Tübingen
Internal Medicine III - Cardiology and Cardiovascular Diseases

Prof. Dr. Meinrad Gawaz (Medical Director)
Otfried-Müller-Straße 10
72076 Tübingen

Phone: +49 (0)7071 29-83688
Fax: +49 (0)7071 29-5749
meinrad [dot] gawaz [at] med [dot] uni-tuebingen [dot] de