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Ageing stem cells loose ability to adhere to stroma

Hartmut Geiger, a biochemist and stem cell researcher at Ulm University Hospital is using genetic methods to investigate the molecular basis of the physiological ageing of haematopoietic stem cells. After having spent a period in Cincinnati, Geiger is currently head of the clinical research group "Molecular and cellular ageing – from the mechanisms of action to clinical perspectives".

Prof. Dr. Hartmut Geiger. © Geiger, UK Ulm
Geiger’s field of interest lies in haematopoietic stem cells and he has previously carried out research into stem cell redifferentiation. He was particularly interested in finding out how he could alter the differentiation behaviour of stem cells in mice. Back in the USA, where he spent 9 years, Geiger was mainly concerned with the ageing of stem cells. He spent a three-year postdoctoral period in a leading genetics laboratory in Lexington/Kentucky under the leadership of Gary van Zant. This period had a decisive influence on his research. As assistant professor at the Cincinnati Children’s Hospital, which is part of the Cincinnati Children's Research Foundation, Geiger continued his research into the ageing and mobilisation of stem cells using genetic methods.

Evidence accumulating over the past decade has proven that there is a measurable and successive functional decline in haematopoietic, intestinal and muscle stem cell activity from adulthood to old age, resulting in a decline of stem cell function in aged humans and mice. As stem cell activity is necessary to replenish lost differentiated cells, it has been hypothesised that the ageing of stem cells results in impaired tissue homeostasis in aged individuals, which might ultimately limit lifespan.

Other activity patterns

Recently, Geiger and his colleagues discovered that the activity of old haematopoietic stem cells (HCS) differed from that of young HCS and that these differences are to a large extent intrinsic to HCS and do not depend on their environment, i.e. stem cell niche. Geiger believes that old HCS are unable to interact effectively with stromal cells, which, in turn, could affect their self-renewal and differentiation potential. Geiger’s findings are based on experiments using normal, physiologically ageing mice. He did not use transgenic or knock-out mice for his investigations.

Important interaction of haematopoietic cells with stromal cells

Freeze imaging of young haematopoietic stem cells (green: old stem cells; red: young stem cells) in their niche. © Hartmut Geiger
Geiger assumes that both young and old HSC interact in the same way with stromal cells, i.e. their interaction pathways do not differ. The researcher from Ulm discovered that aged haematopoietic cells adhere less to stromal cells than young cells do and are no longer able to unequivocally communicate the signals of the niche. The stem cells are less likely to remain in the microenvironment and this could lead to them changing their differentiation pathways.

The data have led to hypotheses that are difficult to test experimentally in vivo, mainly because it is difficult to access the haematopoietic stem cells in their niche. Despite these difficulties, Geiger is able to visualise the altered adhesion ability of old haematopoietic stem cells. Working with a colleague from Magdeburg, Geiger has developed a two-photon microscopy technique with which it is possible to acquire in vivo images of stem cells in their particular niches. Geiger describes the appearance of old HSC as a kind of prickly ball that tends to change its appearance as it becomes more active. “The spines frequently appear and disappear,” said Geiger who has found this out from observing the changes in the cells’ surface or volume over a specific period of time.

Cdc42 is strongly activated

Stem cell ageing
Several proteins that regulate the cell-cell interactions of stem cells have recently been identified. Some studies, including Geiger’s published and unpublished data, suggest that HSC ageing correlates with considerable alterations in the expression of cell adhesion molecules. Geiger also found that the altered interaction might be due to the elevated activity of small RhoGTPase Cdc42 in aged stem cells. In multicellular organisms, this protein controls many signal transduction pathways, and also regulates the actin cytoskeleton. Geiger is now very interested in finding out whether this enzyme is the cause of the cell’s reduced adhesiveness to stromal cells. At present, Geiger cannot exclude this being due to different causes, for example cytokines or other systemic factors. In order to verify his assumption, Geiger plans to modify the Cdc42 protein and hopes that this will affect in vivo stem cell ageing.

Physiological ageing provides correlations

The fact that Geiger has to base his research on hypotheses that are, in turn, based on individual observations is a disadvantage when trying to understand physiological ageing, as this results in correlations rather than clear molecular connections. Ageing research on mice has the advantage that many of the required experimental tools are available, the mice reproduce quickly and a great deal is known about mouse genetics. Some aspects can be transferred directly to humans, others can only be used contextually.

Focus on normal ageing

Geiger’s group of researchers is hoping to gain insights into the physiological ageing of mice using haematopoietic stem cells. This requires the researchers to describe the alterations observed in different mouse strains. This is not a small matter, because, rather than being black and white, the results are somewhat grey. Geiger recognises the importance of comparative investigations for their focus on physiological systems. Although research on knock-out or transgenic mice has its advantages, it must be kept in mind that such extremes do not exist in the human gene pool. The results gained from knock-out or transgenic mice cannot always be used physiologically. Geiger describes his approach as follows: “Cherries from the lower branches are not always the best.”

Data substantiate causal relationship

Geiger believes that there are only a limited number of causal theories to explain stem cell ageing. His genetic studies involving mice have shown that phenotypes which regulate the haematopoietic system also affect an organism’s life expectancy. At present, this is just a correlation, but the overlaps are so striking that a mere mathematical correlation seems rather improbable. The transfer of these findings to the situation in humans is very complex and time-consuming. Working with researchers from Lexington, Geiger has identified a locus that is important for stem cell ageing at the same time as having an impact on the life expectancy of animals. Geiger will continue his work in this basic-research oriented project, because it takes a long time to accumulate substantial evidence to back his assumptions.

Do stem cells change outside of their niche?

Closer to application is Geiger’s research into ways to delay, and potentially halt, stem cell aging. He has found out that old haematopoietic stem cells that are mobilised by cytokines and growth factors develop properties different from those of aged stem cells. This raises the question of what happens when the stem cells are removed from their normal environment and used somewhere else. He cautiously expresses the possibility that the stem cells might rejuvenate. This would mean that stem cells have particular properties in the niche that have a negative effect on them; and vice versa, that it could be concluded that these properties can be altered by removing the stem cells from their physiological niche.

Better ageing in the haematopoietic system

The ultimate goal of Geiger’s research on the physiological ageing of stem cells is to find ways to delay the ageing process, improve the ageing of the haematopoietic system, which is associated with many problems especially in elderly people in whom the reduced generation of red blood cells impairs the adaptive and the non-adaptive immune system and also leads to problems in patients undergoing chemotherapy or suffering from infections. According to Geiger, the blood cells of the non-adaptive immune system are generated by HSC by way of indirect pathways. He also said that there is clear evidence that it is very difficult to effectively generate these blood cells.

Solving puzzles with partners from Ulm

At Ulm University, which is home to one of the few adult stem cell priorities in Germany, Geiger will be able to find many cooperation partners in his search to clarify the correlation between ageing and cancer. He will focus on the haematopoietic system, first in physiological systems and then in genetically modified models. If he is able to come up with physiological explanations as to why older people generally suffer more from leukaemia or cancer, then this would help the researchers to find ways of delaying the ageing process or of adapting cancer therapies to a patient’s age.

Literature: Geiger, H. et al.: Stem Cells, Aging, Niche, Adhesion and Cdc42, in: Cell Cycle 6:8, s. 884-887, 15 April 2007.

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