Developing a human-relevant bone marrow on-a-chip to better understand rheumatoid arthritis and chronic inflammation

Professor Jesmond Dalli

Queen Mary University London

 

I would like to thank Animal Free Research UK and Helpathon for facilitating the adoption of these models and opening my horizons to these exciting systems – Professor Jesmond Dalli, Queen Mary University of London

Inflammation – friend or foe?

Rheumatoid arthritis is an incurable, chronic condition that causes pain, swelling and stiffness in joints, usually in the hands, feet and wrists. The condition affects around 1% of people in the UK and is also associated with other conditions such as cardiovascular disease, osteoporosis, anaemia, and infection.

Inflammation happens when your body’s immune response to infection or injury. When we encounter an invading organism (such as bacteria or viruses) or when we suffer an injury, the cells within our body produce signals that alert surrounding cells, such as white blood cells. This ‘rallying of the troops’ helps to fight, capture or eliminate the invader and to clear debris caused by the damage. Conditions such as rheumatoid arthritis develop when the protective process of inflammation goes awry and persists even though it shouldn’t, for reasons that aren’t fully understood.

Shining a light on the role of the bone marrow inflammatory ‘niche’

Our blood cells begin their life cycle as unspecialised or ‘stem’ cells within bone marrow (the spongy tissue inside bones). They develop through a process called haematopoiesis where the stem cells transition progressively into specialised blood cells with particular functions, for example, red blood cells (which transport oxygen around our body) and white blood cells (which target and destroy bacteria and viruses).

In rheumatoid arthritis, the normal process of blood cell development is disrupted, which renders cells more likely to drive inflammation and cause tissue damage. The reasons behind this disturbance in blood cell development are not fully understood but are thought to be driven by molecules within the microenvironment or ‘niche’ that surrounds the cells.

Replacing animal experiments with a more human-relevant approach to treating inflammatory diseases

One of the barriers to fully understanding the causes of inflammatory diseases has been the heavy reliance on animal experiments, primarily using mice. There are fundamental differences in blood cell development and the progression of inflammation in humans compared with mice, which means findings in mice experiments do not translate to breakthroughs in tackling human conditions.

Another problem is the fact that the spongy bone marrow is encased in bone which makes it hard to access for research. This means that researchers need to remove the bone first which can alter some of the tiny and delicate structures within bone marrow.

To overcome these barriers and shed light on the drivers of inflammation, Professor Jesmond Dalli at Queen Mary University of London is developing and validating an innovative organ-on-a-chip tool, in collaboration with the Emulate company. This comprises a plastic chip with fluid filled channels within which bone marrow cells can grow and interact in an environment that mimics human bone marrow.  This project proposal emerged from the very first animal-free innovation Helpathon in the UK.

The first step will be growing bone marrow cells on the chip. These will then be collected and analysed to ensure that the types and numbers of cells closely reflects the structure of human bone marrow, and that the cells work as they should.

After validating the model, Professor Dalli will use the bone marrow on-a-chip to study the bone marrow niche and in particular, how different cells and molecules interact with each other. This will enable him to shed light on what causes changes in blood cell production and which molecules may be driving inflammation.

The impact of this research

This research could allow unique insights into the causes of inflammatory conditions, such as rheumatoid arthritis, paving the way for the development for new treatments as well as replacing the thousands of animals used in inflammation research.