Epithelial cells play an essential role in asthma research

Epithelial cells line the inside of the airways and alveoli. They play an important role in asthma. Prof.dr. Pieter Hiemstra of the Leiden University Medical Centre (LUMC) is an internationally renowned expert in culturing human epithelial cells. 'With these cultures we can study what happens in asthma and how we can prevent it.' Hiemstra also uses epithelial cells to study the effect of diesel exhaust gases.

Pieter Hiemstra: 'I am very curious by nature. As a high school student, it fascinated me that every living being consists of separate cells. How is that possible? How do they work together? I wanted to understand that. And I still do.' He now heads a research group at the LUMC that studies asthma, among other things, and participates in the international Asthma Prevention Consortium.

In asthma, there is chronic inflammation in the lungs. Epithelial cells play an important role in this. Hiemstra: 'We are investigating what exactly happens and how epithelial cells are involved in the inflammatory response. But also why one child develops asthma and the other does not. We can't study this in humans because we need to study lung tissue. That is why we culture and study different types of epithelial cells in the laboratory.' Hiemstra's group is associated with the lung disease clinic of the LUMC. The cells he cultures come from lung tissue that has been removed from patients, for example during an operation. 'We are very lucky to have human cells available. This allows for faster translation to clinical treatments than working with cells of laboratory animals.'

City bus
Asthma is caused by all kinds of stimuli that 'turn on' the immune system and the epithelial cells. Smoke and exhaust fumes also contribute to this. How this works exactly is not clear. Hiemstra therefore studied the effect of diesel exhaust fumes with the support of Lung Foundation. For this, he used a diesel engine from a modern city bus. With pipes he led the exhaust gases to culture trays in which human epithelial cells grew. This method is unique. Hiemstra: 'Previous research has been done into the effect of certain particles from exhaust gases. These were filtered out, dissolved in a liquid and then brought into contact with epithelial cells. But that doesn't mimic the real situation. Exhaust gas from a city bus does: this is what people really inhale.' Also, the cell cultures were made in such a way that it appeared to the cells as if they were in the lung. The hope was that this would make them react like they do in real lungs. Hiemstra: 'The more realistic the test situation, the more valuable the knowledge we gain from it. And the faster we get to treatments.'

This hope was confirmed. The diesel exhaust fumes caused inflammation. Also, the epithelial cells became more sensitive to infection. And substances were released that arise during stress and that can damage lung tissue. 'This actually happens in the lung tissue as well. This means it is a realistic model. As a result, we gained new knowledge about what exactly is happening. And this helps us to find out which way we should go for a solution.'

Prevent asthma
In the Asthma Prevention Consortium Hiemstra's research group participates in, Lung Foundation brought together top researchers from the Netherlands, Belgium, Germany, England and Australia to find out how we can prevent asthma in some of the children. There are strong indications that this is possible with certain natural products: unprocessed cow's milk, farm dust and specific molecules from parasitic worms. These products seem to make the immune system of children less sensitive; this prevents inflammation and thus asthma. The top researchers are now studying exactly how this works in order to arrive at treatments.

To prevent asthma in the future, Hiemstra is now broadly deploying his expertise on epithelial models: epithelial cells are involved in many of the research projects. 'Conversely, I am gaining a lot of knowledge about the effects of cow's milk, farm dust and parasitic worms. And we exchange practical lab skills internationally. This collaboration enriches and speeds up research.'

Protect children
An example. There is a link between genetics (our DNA) and asthma. Children with a certain variant of DNA are susceptible to asthma. But why? 'By sharing knowledge, I was able to solve a piece of the puzzle with our epithelial models. Epithelial cells with a predisposition to asthma appear to produce a certain molecule (that is involved in inflammatory reactions) differently.' Another research group had discovered that farm dust does not protect everyone against asthma, but especially children with the DNA variant that makes them prone to asthma. Hiemstra: 'By combining knowledge, we discover which children we can protect and how.'

Indispensable tools
Hiemstra's epithelial cultures are therefore indispensable tools. And they come in different shapes, or 'models'. If you want to know whether epithelial cells respond to a certain substance, a culture dish with epithelial cells is sufficient. When a realistic situation is necessary, it is better to use the chip model developed in Hiemstra's laboratory. Hiemstra: 'In the chip model epithelial cells grow in an environment that resembles lung tissue, in a flexible gel culture that is stretched rhythmically, as occurs during respiration.' Also, Hiemstra cultures so-called mini-organs or organoids: small pieces of epithelial tissue that develop from stem cells. 'If you have material with only a few cells in it, it is difficult to grow epithelial cells in culture dishes. But a few cells are enough to grow them quickly in an organoid. You then transfer them to the culture dishes or chips.'

Hiemstra is optimistic about the future. 'The development of chip models, for example, is going fast. A model is being built that allows you to study multiple organs at the same time.' This is relevant for asthma also. For instance: the lungs are influenced by the gut. This releases substances to which epithelial cells and immune cells in the lungs respond. How this works exactly is still unclear. 'We can then test the effect of unprocessed cow's milk in a more realistic situation,' says Hiemstra. 'I am hopeful that this will accelerate our research further.'

Direct curiosity
Whenever Hiemstra finds a new answer, new questions also arise, he acknowledges. 'But that is stimulating. Each answer opens several new doors. The trick is to follow those doors that offer opportunities for relevant insights and treatments. And that happens within the Asthma Prevention Consortium. Lung Foundation directs researchers' curiosity towards solutions for children with asthma. For me personally, it enhances my enthusiasm for my profession.'

Text: Karin Postelmans