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Regenerative medicine for the treatment of radiation injury

Many tumours can be effectively treated with radiotherapy. However, this type of treatment might also cause alterations in healthy tissue. Less invasive regenerative therapies might be able to repair such damage.

It is always a question of weighing up the pros and cons – if a life-threatening tumour can only be effectively treated with radiotherapy, necessary evils in the form of fibroses are tolerated. Nevertheless, for many years doctors have been investigating how radiation damage like this can be treated. Regenerative medicine is the first available technique to offer an excellent possibility of repairing such damage.

This possibility has arisen thanks to the clarification of the function of the fibrocytes. These connective tissue cells play an important role in the development of fibroses. There are two types of fibrocytes in the healthy tissue, which exist in equal concentrations, regardless of a person’s age: immature fibroblasts and mature functional fibrocytes occur in the human body at a ratio of 2:1. Radiation leads to the increased generation of functional fibrocytes from fibroblasts.

Ionising radiation induces the formation of functional fibrocytes

This poses a big problem because functional fibrocytes produce large quantities of collagen. In practice, this means that the increased number of functional fibrocytes leads to quantities of collagen far in excess of those required for normal tissue function. Professor Dr. H. Peter Rodemann, who is a radiobiologist at the Department of Radiation Oncologyat the University of Tübingen (UKT), gives an impressive description of the consequences of lung tumour irradiation: "In very sensitive patients, the lung is practically cemented with collagen." Radiation of tumours in the head and neck area also leads to the alteration of tissue, for example in the mouth mucosa. This might quickly lead to mucositis, which might eventually lead to ulceration (an open wound that only heals with difficulty) due to the death of epidermal cells.

Sequenceof fibroblast-fibrocyte differentiation (Figure: Department of Radiation Oncology; University of Tübingen)

Sequenceof fibroblast-fibrocyte differentiation (Figure: Department of Radiation Oncology; University of Tübingen)

These side effects in the mouth mucosa interfere with the progress of radiotherapy as Rodemann explains: "Although not all patients are equally sensitive to radiation, it still sometimes happens that radiotherapy has to be stopped due to the negative effects it creates. The tumour then starts to grow again and the therapy is therefore less successful." Rodemann hopes to be able to prevent this unwanted causal chain by using regenerative approaches. Rodemann’s team is working on methods that help balance out the interaction of fibrocytes and keratinocytes. His long-term goal is to use regenerative methods, for example by injecting adult stem cells, to repair tissue damage.

In order to do this, Rodermann and his team need to gain a perfect understanding of the network of molecular mechanisms involving functional fibrocytes and keratinocytes. An important aspect is the investigation of signalling pathways that have an effect on the fibroflast/fibrocyte system. The cytokine TGFß1 is a key molecule, which governs signal transduction that eventually leads to fibrosis. The radiobiologists at the University Hospital of Tübingen are currently investigating the molecular and cellular mechanisms underlying these processes.

An understanding of fibrocytes promotes the development of skin substitutes

Reconstruction of a skin equivalent in a 3D carrier (Photo: Hospital of Radiation Oncology, University of Tübingen)

Reconstruction of a skin equivalent in a 3D carrier (Photo: Hospital of Radiation Oncology, University of Tübingen)

The results achieved by the radiobiologists also contribute to the development of autologousi skin replacements used, for example, in the treatment of chronic wounds. "In order to be able to produce an authentic skin substitute in vitroi from a keratinocyte culture, fibroblast and functional fibrocytes have to be used at their natural ratio of 2:1," said Rodemann. In cooperation with Prof. Dr. Oliver Rennekampff from the Casualty Hospital in Tübingen, Rodemann is working on the development of an autologous, two-part skin substitute that already shows a well-structured epidermal structural and presence of a dermal equivalent. "We are able to achieve about ten to 20 percent of what happens in nature," said Rodemann describing the current state of research. Considering that the field of regenerative medicine is still very new, this development already represents excellent progress.

leh - 1.10.2006
© 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 of Tübingen
Radiobiology and Molecular Environmental Research

Prof. Dr. H. Peter Rodemann
Röntgenweg 11
72076 Tübingen

Phone: +49 (0)7071-298 5962
Fax: +49 (0)7071-29 5900
hans-peter [dot] rodemann [at] uni-tuebingen [dot] de