Air sacs in the lungs called alveoli are crucial for gas exchange and provide an important barrier against inhaled viruses and bacteria that cause respiratory diseases like flu and tuberculosis (TB). However, there remains a gap in developing immunocompetent and experimentally accessible alveolar systems to study human respiratory diseases.
In a new study published in Science Advances titled, “Autologous human iPSC–derived alveolus-on-chip reveals early pathological events of Mycobacterium tuberculosis infection,” researchers from the Francis Crick Institute and AlveoliX have developed what they describe as the first human lung-on-a-chip model using stem cells taken from a single human donor. The chip can simulate breathing motions and lung disease in an individual, holding promise for testing treatments for infections like TB and delivering personalized medicine.
Due to its significance in homeostasis and promise for drug delivery, many in vitro human models have been developed to circumvent the differences in anatomy, immune cell composition, and disease pathogenesis between human and animals. Organ-on-chip technologies have emerged as predictive tissue modeling tools and reliable alternative to animal testing.
“Given the increasing need for non-animal technologies, organ-on-chip approaches are becoming ever more important to recreate human systems, avoiding differences in lung anatomy, makeup of immune cells and disease development between animals and humans,” said Max Gutierrez, PhD, principal group leader of the host-pathogen interactions in tuberculosis laboratory at the Crick and corresponding author of the study.
“Composed of entirely genetically identical cells, the chips could be built from stem cells from people with particular genetic mutations. This would allow us to understand how infections like TB will impact an individual and test the effectiveness of treatments like antibiotics,” he continued.
Lung-on-a-chip models have traditionally been made of a mixture of patient-derived and commercially available cells which are unable to replicate lung function or disease progression of a single individual.
The authors produced type I and II alveolar epithelial cells and vascular endothelial cells from human-induced pluripotent stem cells (iPSCs). To create an air sac barrier, these cells are separately grown on the top and bottom of a very thin membrane in a device manufactured by biotechnology company, AlveoliX. The company also designed specialized machines to impose rhythmic three-dimensional stretching forces on the recreated air sac barrier, mimicking the motion of breathing.
In the chips infected with TB, the team reported large macrophage clusters containing necrotic cores, a group of dead macrophages in the center surrounded by live macrophages. Eventually, five days after infection, the endothelial and epithelial cell barriers collapsed, showing that the air sac function had broken down.
Jakson Luk, PhD, postdoctoral fellow at the Crick and first author of the study emphasized that TB is a slow-moving disease, with months between infection and the development of symptoms. Understanding the early stages of disease progression is a rising need.
“We were successfully able to mimic these initial events in TB progression, giving a holistic picture of how different lung cells respond to infections,” said Luk. “We’re excited that the new model could be applied to a huge range of research, such as other respiratory infections or lung cancer, and we’re now looking at refining the chip by incorporating other important cell types.”
