Human mini-lungs developed by scientists at the University of Manchester can mimic the response of animals when exposed to certain nanomaterials.
The study at the University’s NanoCell Biology Laboratory at the Center for Nanotechnology in Medicine is published in the influential journal Nano Today.
Although not expected to fully replace animal models, human organoids could soon lead to significant reductions in the number of research animals, argues the team led by cell biologist and nanotoxicologist Dr Sandra Vranic.
Grown in a dish from human stem cells, lung organoids are multicellular, three-dimensional structures that aim to recreate key features of human tissues, such as cellular complexity and architecture.
They are increasingly being used to better understand various lung diseases, from cystic fibrosis to lung cancer and infectious diseases including SARS-CoV-2.
However, their ability to capture tissue responses to nanomaterial exposure has so far not been demonstrated.
To expose the organoid model to carbon-based nanomaterials, Dr Rahaf Issa, lead scientist in Dr Vranic’s group, developed a method to precisely dose and microinject nanomaterials into the lumen of the organoid.
It simulated the actual exposure of the apical pulmonary epithelium, the outermost layer of cells that line the respiratory passages inside the lungs.
Existing animal research data have shown that one type of long and rigid multiwalled carbon nanotubes (MWCNTs) can cause adverse effects in the lungs, leading to persistent inflammation and fibrosis – a severe type of irreversible lung scarring.
Using the same biological endpoints, the group’s human lung organoids showed a similar biological response, which validates them as tools for predicting nanomaterial-driven responses in lung tissue.
Human organoids allowed a better understanding of the interactions of nanomaterials with the model tissue, but at the cellular level.
Graphene oxide (GO), a flat, thin and flexible form of carbon nanomaterial, was found to be momentarily trapped out of harm’s way in a substance produced by the respiratory system called secretory mucin.
In contrast, MWCNT induced a more persistent interaction with alveolar cells, with more limited mucin secretion and leading to fibrous tissue growth.
In a further development, Dr. Issa and Vranic based at the University’s Center for Nanotechnology in Medicine are developing and studying a pioneering human lung organoid that also contains an integrated immune cell component.
Dr Vranic said: “With further validation, prolonged exposure and the incorporation of an immune component, human lung organoids could significantly reduce the need for animals used in nanotoxicology research.
“The 3Rs of replacement, reduction and improvement, developed to encourage humane animal research, are now enshrined in UK law and many other countries.
“Public attitudes consistently show that support for animal research depends on implementation of the 3Rs.”
Current “2D tests” of nanomaterials using 2D cell culture models provide some understanding of cellular effects, but are so simplistic that they can only partially depict the complex way cells communicate with each other. It certainly does not represent the complexity of the human lung epithelium and may misrepresent the toxic potential of nanomaterials, for better or worse.
“Although animals will continue to be needed in research for the foreseeable future, ‘3D’ organoids are nevertheless an exciting prospect in our research field and in research in general as a human equivalent and an animal alternative.”
Professor Costas Kostarelos, Chair of Nanomedicine, University of Manchester
Source:
Journal Reference:
Issa, R., et al. (2024). Functional human lung organoids model lung tissue response to carbon nanomaterial exposures. Nano Today. doi.org/10.1016/j.nantod.2024.102254.
