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Haematopoietic stem cells and their clinical application

There are high expectations for stem cells in the treatment of diseases for which no curative treatment is currently available. However, it would be unrealistic to expect quick results. Taking one the first successful peripheral haematopoietic stem cell transplantations carried out around 25 years ago on a cancer patient in Heidelberg as an example, Professor Anthony Ho shows that the development of stem cell-based therapies requires solid research and a great deal of patience.

© University Hospital Heidelberg

In November 2010, international stem cell researchers and transplantation specialists came together for the 15th time at the Advances in Stem Cell Transplantation symposium organised alternately by the University of Heidelberg and the University of California San Diego.

This year, the meeting was held at the same time as the University of Heidelberg's 625th anniversary celebrations, the oldest university in Germany. In addition, the scientists present celebrated another anniversary of which the symposium organiser, Prof. Dr. Anthony D. Ho, Medical Director of the Department of Medicine V of Heidelberg University Hospital, can be truly proud: exactly 25 years ago in November 1985, Heidelberg surgeons carried out the first successful transplantation of stem cells removed from circulating (peripheral) blood.

25 years of peripheral haematopoietic stem cell transplants

Removal of haematopoietic stem cells from a patient in the Heidelberg Transplantation Centre © University Hospital Heidelberg

The patient, Sebastian Gärtner, who suffered from very malignant non-Hodgkin lymphoma (Burkitt lymphoma) and who, for medical reasons, could not undergo bone marrow transplantation, which was already an established method 25 years ago, is now in excellent health and has been able to participate in celebrating the 25th anniversary of his cure.

Until 1985, the bone marrow was regarded as the only source of haematopoietic stem cells for clinical transplantation. However, Martin Körbling and Theodor Fliedner had been able to show in animal experiments that stem cells could be derived from circulating blood using a kind of dialysis. After transplantation, these stem cells settle in the bone marrow niches, where they proliferate and start producing red and white blood cells once all the malignant cells in the bone marrow have been destroyed through high-dose chemo- and radiotherapy. "Sebastian Gärtner was the first patient to undergo our innovative treatment concept," said Ho, who published a groundbreaking study on peripheral blood stem cell transplantation (PBST) in humans in cooperation with his colleagues Martin Körblin, Bernd Dörken and Werner Hunstein (formerly medical director). Ho believes that the greatest advantage of PBST over bone marrow transplants is the shorter recovery time after the operation; the first patient only took ten days to fully recover instead of the standard three to four weeks that is usual for bone marrow transplants. Patients do not need a general anaesthetic either. One disadvantage of PBST is that haematopoietic stem cells are very rare in peripheral blood, which means it is necessary to entice them out of their stem cell niche in the bone marrow and mobilise them.

One of the largest transplantation centres for haematopoietic stem cells

Prof. Dr. Anthony D. Ho, Chair of the Department of Medicine V. © University Hospital Heidelberg

The use of haematopoietic stem cells from circulating blood has since become a standard method, and the Department of Haematology, Oncology and Rheumatology at the University Hospital Heidelberg is now one of the largest haematopoietic stem cell transplantation centres in Germany, transplanting around 320 patients per year. Since 1997, the hospital has not only carried out autologous transplantations with the patients' own stem cells, but it also carries out successful allogeneic transplantations involving stem cells from suitable siblings or unrelated donors. This therapy is often the only curative treatment for patients with aggressive forms of leukaemia, lymph node cancer or multiple myeloma. Allogeneic stem cell transplantation causes great strain for the patients and is associated with many risks, which is why it was initially only used for relatively young patients. However, due to progress in the transplantation procedures, allogeneic stem cell transplantation is now also available for much older patients, a development that has received scant attention because it is possibly one of the less spectacular advances made in the field of medicine, said Ho. The Heidelberg Stem Cell Registry (HSR), which works with international institutions, was established in 2001 in cooperation with the Institute of Transplantation Immunology at the University of Heidelberg (Director: Prof. Dr. Gerhard Opelz). The registry currently stores information from more than 50,000 potential stem cell donors, and thus makes a considerable contribution to the rapid identification of a matching donor.

After the first PBST in Heidelberg, it took another ten years for the German statutory health insurance funds to take on the transplantation costs, which it eventually did from 1995 onwards. "Those who work on the development of stem cell-based therapies need a lot of time and a great deal of resources," explained Ho speaking at the Autumn Forum of the German Society of Regenerative Medicine held on 12th November 2010. "But the effort is definitely worth it." Ho recommends that all people who feel that suitable therapies are never developed quickly enough should take a look at the history of stem cell transplantation.

The origin of stem cell research

Alexander A. Maximow wearing the uniform of a Russian Army general, picture taken between 1903 and 1910. © Archive of the Pirogov National Medical Centre, Moskva.

One year ago, haematologists all over the world celebrated the 100th anniversary of the term and concept "stem cell". In 1909, the famous Russian haematologist Alexander A. Maximow proposed the word "stem cell", and also developed and introduced the theory of stem cell mobilisation and circulating stem cells in the blood. He published his ideas in a book, written in German, entitled "Der Lymphozyt als gemeinsame Stammzelle der verschiedenen Blutelemente in der embryonalen Entwicklung und im postfetalen Leben der Säugetiere" (The lymphocyte as a stem cell, common to different blood elements in embryonic development and during the post-foetal life of mammals) (published in "Folia Haematologica", vol. VIII, in Berlin).

It then was another fifty years before the American Edward Donall Thomas carried out groundbreaking research leading to the technique of bone-marrow transplantation for the treatment of patients suffering from leukaemia or other cancers of the blood. He was awarded the Nobel Prize in Physiology and Medicine for this research in 1990. The actual proof of the existence of blood stem cells in the bone marrow was made in 1961 by the Canadian scientists James E. Till, Ernest McCulloch and Lou Siminovitch, but it took another twenty years before bone marrow transplants became widely used for the clinical treatment of leukaemia. In the meantime, the Russian researcher Alexander J. Friedenstein and his team discovered that mesenchymal stem cells (MSC) in the bone marrow stroma were fibroblast precursor cells. However, MSC are not only important for supporting tissue, but are also found in bones, cartilage, muscles and fatty tissue. Over the last few years since they were found to play an important role in the development of precursor blood cells in the bone marrow, MSC have become a major focus of research. According to current findings, the binding between HSC and MSC in the bone marrow stem cell niche is of crucial importance for the self-renewal potential of blood stem cells. Researchers are therefore looking for ways to intervene in these binding mechanisms in order to develop new innovative strategies for the more effective mobilisation of blood stem cells. Since cancer stem cells use the same mechanisms to hide away, this research provides starting points for future therapies that might protect patients against late leukaemia recurrences. Ho explained that the goal is to expel the malignant "dormant" cells from their niches and render them harmless.

Further information:
Prof. Dr. Anthony D. Ho, Medical Director
Department of Medicine V - Haematology - Oncology - Rheumatology
University Hospital Heidelberg
Im Neuenheimer Feld 410
69120 Heidelberg
Tel.: +49 (0)6221-56 37 04 2
Fax: +49 (0)6221-56 50 54
E-mail: ursula.schoettler(at)med.uni-heidelberg.de
Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/haematopoietic-stem-cells-and-their-clinical-application