At present, to screen for compounds that might show promise in tackling disease, researchers have to rely on animal models like specially-bred lab mice. However, many candidate drugs that pass such tests are later rejected, and some that do not pass could be effective in humans. This leads to delays, increased costs and lost opportunities to the development of urgently needed new treatments.
Image credit: Nick Hannan, University of Cambridge
Stem cells are cells that have the potential to become any cell in the body. Scientists have developed various ways to coax this transformation and also of sourcing stem cells. Progress in this field is showing promise as an avenue for creating realistic models of human tissue derived from human cells – so-called “organoids” or “mini-organs.”
For example, we recently reported a study that showed how a new 3D organoid culture system promises to transform pancreatic cancer research and treatments.
And in another earlier report, we described how scientists created fully functional organoids of human intestines.
Now a team at the University of Cambridge in the UK has successfully created “mini-lungs” as a way forward to research and test new drugs to fight the debilitating lung disease cystic fibrosis.
Now, writing in the journal Stem Cells and Development, a team at the University of Cambridge in the UK describes how it successfully created “mini-lungs” as a way forward to research and test new drugs to fight the debilitating lung disease cystic fibrosis.
Using stem cells derived from skins of cystic fibrosis patients, the scientists generated organoid models of the distal part of lung tissue, the part that forms the airways where gases are exchanged with the environment. Study leader Dr. Nick Hannan, explains:
“In a sense, what we’ve created are ‘mini-lungs.’ While they only represent the distal part of lung tissue, they are grown from human cells and so can be more reliable than using traditional animal models, such as mice. We can use them to learn more about key aspects of serious diseases – in our case, cystic fibrosis.”
Cystic fibrosis is a condition where the lungs produce too much thick mucus causing breathing problems and increasing the risk of respiratory infection. The disease is monogenic – that is it is caused by a single gene fault, although the mutation can be different in different patients.
Recent advances in treatments are helping to extend the lives of people with cystic fibrosis, who tend to have a shorter average lifespan.
For their study, Dr. Hannan and colleagues, of the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, generated stem cells from the skin cells of patients with the most common form of cystic fibrosis that arises from a fault in the CFTR gene known as the delta-F508 mutation. The mutation is the cause of cystic fibrosis in around three quarters of UK patients.
The team reprogrammed the skin cells to revert to a state known as “induced pluripotent” – making them into stem cells that are poised to develop into any type of cell in the body.
Using the induced pluripotent state cells (iPSCs), the team then recreated conditions similar to what happens when the human embryo develops different types of lung tissue – a process called “gastrulation”.
During gastrulation, the embryo grows the endoderm and then the foregut, from which the lungs emerge and form into different tissue types, including those furthest away from the point of origin – the “distal” lung tissue of the airways where gases are exchanged between the body and the environment.
The distal tissue is often the part of the lungs that causes problems in diseases like cystic fibrosis, some forms of lung cancer and emphysema.
In people with the delta-F508 mutation, the CFTR protein in their airway tissue does not fold correctly so it is not expressed properly on cell surfaces. This disrupts the function of the chloride channel.
Chloride channels are pore-forming surface proteins that allow chloride ions to move in and out of the cells of the airway tissue. If they malfunction, cells cannot move water to the lining of the lungs, causing mucus to become too sticky. This results in breathing difficulties and higher risk of bacterial infection – which in the longer terms leads to scarring or “fibrosis.”
To test how well their mini-lungs replicated the conditions of cystic fibrosis in patients with the delta-F508 mutation, the team used a fluorescent dye that is sensitive to chloride. With the help of the dye they were able to demonstrate that compared to healthy cells, the ones in the mini-lungs had restricted chloride movement.
The team then used the dye system and the mini-lungs to show that adding a small molecule helped the diseased cells to move chloride more easily – as well as healthy cells. Dr. Hannan concludes:
“We’re confident this process could be scaled up to enable us to screen tens of thousands of compounds and develop mini-lungs with other diseases such as lung cancer and idiopathic pulmonary fibrosis. This is far more practical, should provide more reliable data and is also more ethical than using large numbers of mice for such research.”
Most of the funding for the study came from the European Research Council, the National Institute for Health Research Cambridge Biomedical Research Centre and the Evelyn Trust.
Meanwhile, Medical News Today recently learned how another team at the University of Texas at Austin has developed a new way of testing for the most common cause of life-threatening infection in cystic fibrosis patients, a bacterium called Pseudomonas aeruginosa.
The new method replicates the exact environment in which the bacterium spreads in the mucus in the lungs of a person with cystic fibrosis, allowing the genes that appear to be necessary for its survival to be identified.