Single-donor “lung-on-chip” breathes new life into disease modeling and personalized medicine
A new “lung-on-chip” model, consisting solely of genetically identical cells derived from a single person, has advanced our understanding of tuberculosis, opening the door to personalized treatments.
Researchers at the Francis Crick Institute (London, UK) and AlveoliX (Bern, Switzerland) have developed a single-donor human induced pluripotent stem cell (IPSC)-derived lung-on-chip model, which can mimic breathing and simulate lung disease in an individual. It therefore holds promise for personalized medicine in the treatment of lung cancer and respiratory infections, such as tuberculosis.
Alveoli –balloon-like air sacs in the lungs – are an essential first line of defence against infection. Traditionally, attempts to understand their inner workings have been limited to animal studies that, while incredibly useful, do not paint a perfect picture of respiratory processes in our own species.
Organ-on-chip technologies represent a promising alternative. However, multicellular airway models have, until this point, been based on cell lines and primary cells, or a combination of both, rendering them unable to fully replicate the lung function or disease progression of a single individual.
In Focus: New approach methodologies
New approach methodologies (NAMs) are rapidly being adopted in the early stages of therapeutics development because they offer researchers more human-relevant models. NAMs encompass a wide range of tools from in vitro to in silico models, offering a varied and innovative toolbox to replace outdated animal models.
To circumvent this, the researchers engineered a physiologically inspired human lung-on-chip containing genetically identical cells. Firstly, they used human IPSCs to produce type I and II alveolar epithelial cells. These were then grown on top of a very thin membrane in a device manufactured by AlveoliX, while vascular endothelial cells – grown from the same IPSCs – populated the bottom of the membrane.
The result was an air sac barrier where both layers of cells developed on their own and were sourced from a single donor.
Taking things a step further, the team used a specialized machine designed by AlveoliX, the AXBreather to impose rhythmic three-dimensional stretching forces on the barrier, imitating breathing. Scanning electron microscopy revealed that this stimulated the formation of microvilli.
The new lung-on-chip was then used as an early infection model for tuberculosis. The scientists added macrophages produced from the stem cells of the original donor, before infecting them with the pathogen Mycobacterium tuberculosis.
In the chips simulating the disease, both epithelial cells and macrophages were infected by the bacterium, and cell death predominantly took place in the macrophages. The team observed large macrophage clusters containing necrotic macrophages at their core, surrounded by live macrophages. Five days after infection, the air sac barriers collapsed.
By combining their lung-on-chip with genetically engineered induced pluripotent stem cells, they also identified a cell type-dependent role for the autophagy gene ATG14 in regulating macrophage survival during M. tuberculosis infection.
As well as broadening our knowledge of the mechanisms of tuberculosis infection, the study presents a viable human alveolar model that bypasses some of the shortcomings of existing technologies and could therefore prove valuable in studying lung diseases and therapies.
“We could now build chips from people with particular genetic mutations to understand how infections like [tuberculosis] will impact them and test the effectiveness of treatments like antibiotics,” study author Jakson Lux theorized.
“The chip supports the big push into personalised medicine,” added Max Gutierrez, senior author of the paper. “It could help us understand the impact of genetics on whether a treatment is effective or not.”