Counteracting hematopoietic ageing by pharmacological inhibition of TGFbeta and IL-6 signaling

Stem cells are a special type of cell with the ability to make many other types of cell. As we age, the stem cells in our bone marrow stop working properly. This means that they are no longer able to make red blood cells (the cells that transport oxygen around the body) or white blood cells (the cells that help our body fight infections), quite as efficiently. This leads to a variety of health complications, from a weak immune system that can no longer fight infections, to a reduction in cognitive and cardiovascular ability and muscle strength.

The functioning of any cell in our bodies, including bone marrow stem cells, depends on how their DNA is controlled. All cells have the same DNA code in them, but read this code in different ways. The code is divided into portions of information, like words in a sentence, called genes. Each gene tells the cell to do a different task, or make a different important component.

To understand why ageing has this effect, in a previous project we compared the genes are turned on and off in bone marrow stem cells obtained from young and old mice. We discovered that there are two sets of genes that seem to be more active in old bone marrow stem cells. To check that these genes were really important, we looked at the 'production' line of cell components that they code for. We found that if we tampered with these production lines, we were able to revert some of the age-related effects in the bone marrow cells.

In this project, we want to understand better how we can adjust these production lines to really revert the effects of ageing in bone marrow stem cells. In particular, we want to understand how tampering with one of these production lines (known as TGFbeta signalling pathway) can lead to an increased production of white blood cells and better protection against infections. We are also interested in understanding how tampering with both production pathways can increase the production of red blood cells.

Ultimately, we hope that by understanding better how these two production lines interfere with the normal work of bone marrow stem cells, we may be able to devise ways to reverse it, and hopefully help patients affected by these conditions.

Ageing of the hematopoietic system is associated with declining erythropoiesis and lymphopoiesis, leading to decreased adaptive immunity and frequent anemia, together contributing to multiple age-related morbidities, including cognitive decline, decreased muscle strength, cardiovascular problems and susceptibility to infection.

Using an unbiased approach to the identification of changes to the aged bone marrow microenvironment we identified the IL-6 and TGFbeta signalling pathways as up-regulated. We found that TGFbeta signaling plays a key role in sustaining increased HSC platelet priming in aged mice, as pharmacological inhibition of TGFbetaR1 lead to decreased HSC numbers and strong depletion of HSC platelet priming. Importantly, this was accompanied both by increased lymphoid priming of MPPs and rebalancing of HSC output in competitive repopulation assays, indicating that TGFbetaR1 inhibition provides a means to improve lymphopoiesis in aged hematopoiesis. In the present proposal we will measure the stability of the rebalancing of HSC lineage output after TGFbetaR1 inhibitor withdrawal, as well as the ability of TGFbetaR1 inhibition to improve the output of naïve, antigen-responsive lymphocytes.

In addition, we observed that both IL-6 and TGFbeta signalling contributed to the age-dependent decrease in erythropoiesis: inhibition of IL-6 using a neutralising antibody reversed the age-dependent decline in erythroid progenitor function, whereas TGFbetaR1 inhibition improved erythroid progenitor output. We will therefore now test the ability of combined IL-6 and TGFbetaR1 inhibition to improve erythropoiesis, and in particular to restore peripheral blood hemoglobin levels, as this is the key parameter correlated to age-related multimorbidity.

These studies will determine if TGFbetaR1 and IL-6 inhibition has therapeutic potential in aged hematopoiesis, and since drugs targeting these pathways are available, the potential for clinical application.

Given the considerable and increasing health burden associated with immune-senescence, we anticipate that there will be considerable interest for translational research and drug development in this area. The proposed research therefore has the potential to benefit the UK biotech area, and we will interact with the appropriate structure within Oxford and surroundings to achieve this (Oxford Innovation, Lab282 (www.lab282.org)).

This project also has the potential to improve population health, a significant benefit to the general public, and to reduce hospitalisation costs for respiratory infections, another public benefit. This will be explored in collaboration with local haematologists through the Oxford Biomedical Research Centre and Oxford Centre for Hematology.