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Early warning signals of ageing in stem cells

The large international project SyStemAge is specifically focused on the role of stem cells in ageing and age-related diseases such as myelodysplastic syndrome and B-cell chronic lymphocytic leukaemia. Coordinated by the European Molecular Biology Laboratory and the Heidelberg University Hospital, the SyStemAge consortium seeks to identify the causes and molecular pathways associated with the processes of ageing on the stem-cell level as well as developing novel strategies for the early treatment of age-related disorders.

Human mesenchymal bone-marrow stem cells © Heidelberg University Hospital

The regenerative power of a living organism is linked to the potential of its stem cells to replace damaged tissue. Somatic stem cells (tissue stem cells) arise directly from the pluripotent cells of early embryos and divide, or have the potential to divide, for as long as the tissue exists – which basically means for as long as an organism lives. In other words, organisms are as old as their stem cells. The regenerative power of organisms decreases and a person’s susceptibility to disease increases with age, in particular the susceptibility to infectious diseases, chronic inflammation and many types of cancer. This susceptibility to disease is associated with the increasing weakening of the immune system. According to Dr. Anne-Claude Gavin from the European Molecular Biology Laboratory (EMBL) in Heidelberg, the immune system is “the product of interactions among haematopoietic stem cells (HSC), endothelial cells (EC) of the vascular and lymphatic vessels and the microenvironment in the bone marrow, among others.” The loss of regenerative functions and propensity to cancer can therefore be interpreted as harbingers of ageing at the somatic stem cell level.

The SysStemAge project

Dr. Anne-Claude Gavin © EMBL

The international research project SyStemAge, which is coordinated by Anne-Claude Gavin, head of a group of researchers and senior scientist in the Department of Structural and Computational Biology at EMBL, is focused on ageing processes in haematopoietic stem cells and the bone marrow. The SyStemAge consortium brings together eleven research groups from Germany, England, Spain, Japan and Russia and was started in January 2013. It is funded for a period of five years by the 7th EU Framework Programme under the category Health.

The researchers apply systems biology approaches to HSC and their stem cell niche in the bone marrow with the aim of developing a systems-level understanding of the molecular mechanisms of ageing in somatic stem cells and their microenvironment.

The SyStemAge consortium is also aimed at investigating the age-related changes of stem cells with regard to the development of bone marrow diseases and the ways to correct these age-related alterations and diseases. The researchers will specifically focus on two diseases occurring mainly in older people: 

  • First, myelodysplastic syndromes (MDS), which are disorders of stem cells in the bone marrow. Patients with MDS often develop leukaemias. In advanced MDS, the number and quality of blood-forming cells irreversibly declines.

  • Second, B-cell chronic lymphocytic leukaemia (B-CLL), which is a malignant lymph-node disorder caused by the excessive proliferation of B lymphocytes. B-CLL is the most common type of leukaemia in adults.

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

The SyStemAge consortium involves basic biomedical research institutes, university departments and systems biology research groups, as well as two small- and medium-sized companies with proven expertise in the translation of biomedical models into new strategies for the treatment of human diseases. With their outstanding experience in biomedical modelling and complex systems theory and in the application of molecular and cell biology approaches, Dr. Gavin and her EMBL team are specifically qualified for coordinating the project. Their work on biomolecular networks and the organisation of proteomes and metabolomes has achieved enormous international recognition. 

The medical side of the project is coordinated by Professor Dr. Anthony Dr. Ho, medical director of the Department of Haematology, Oncology and Rheumatology (Internal Medicine V) at Heidelberg University Hospital. Ho is a pioneer in clinical research and the application of haematopoietic stem cells. He played a key role in the first successful transplantation of peripheral blood HSC into a cancer patient as early as 1985. 

Defective stem cell ageing in cancer

B lymphocytes in B-cell chronic lymphocytic leukaemia. © Heidelberg University Hospital

“One of the major goals of the project is to find out whether it is possible to influence the ageing processes of stem cells,” said Gavin. In order to do this, the researchers need to build up knowledge about the molecular alterations in the stem cells and their neighbouring cells in the stem cell niche of the bone marrow, including post-translational modifications and DNA damage that accumulates as people age and which are seen as the causes of the decreasing regenerative power of stem cells.

But why is this so? Is it because the accuracy and efficiency of cellular repair systems decreases? Which molecular signalling pathways control ageing processes? Why do some elderly people develop bone marrow diseases while others don’t? Are there characteristic markers that enable a distinction to be made between normal and defective stem-cell ageing? These are some of the questions the interdisciplinary SyStemAge consortium seeks to answer over the coming years using state-of-the-art technology and methods. The researchers will use novel systems biology approaches to investigate the broad range of connected and interacting factors.

PD Dr. Thomas Luft © Heidelberg University Hospital

The researchers also hope to gain a better understanding of the pathogenesis and causes of age-related bone marrow disorders such as MDS and B-CLL. “We would like to find out how these two diseases are linked with the ageing of stem cells and whether the diseases are caused as a result of premature stem-cell ageing,” said Ho. Ho’s group of researchers works with a team headed up by Dr. Thomas Luft (head of the “Myelodysplastic Syndrome Task Force” at Heidelberg University Hospital) with the aim of analysing the genome of stem cells of different ages, i.e. the stem cells of newborn babies as well as those of people over 70. The researchers are also comparing the genomes of patients with MDS and B-CLL with those of healthy volunteers of the same age group in order to glean information on DNA damage that accumulates over time and on normal and defective ageing processes of human stem cells.

All these data might provide the scientists with information on how to counteract the defective ageing of bone marrow stem cells using new drugs. The results could also potentially be of huge diagnostic importance if markers of age-related disorders are found. This would enable the identification of early warning signals of ageing in human stem cells long before visible symptoms of age-related disorders and impairments appear.

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/early-warning-signals-of-ageing-in-stem-cells