First breathing lung-on-chip developed using genetically identical cells

Amazing stuff!

"Researchers at the Francis Crick Institute and AlveoliX have developed the first human lung-on-chip model using stem cells taken from only one person. These chips simulate breathing motions and lung disease in an individual, holding promise for testing treatments for infections like tuberculosis (TB) and delivering personalized medicine. ...

Until now, these lung-on-chip devices have been made of a mixture of patient-derived and commercially available cells, meaning they can't fully replicate the lung function or disease progression of a single individual.

In the study, the team ... developed a new lung-on-chip model that contains only genetically identical cells derived from stem cells from a single donor. ...

To further simulate the human lung, AlveoliX has designed specialized machines to impose rhythmic three-dimensional stretching forces on the recreated air sac barrier, mimicking the motion of breathing. This stimulates the formation of microvilli, a key feature of alveolar epithelial cells, to increase surface area for lung functions ..."

"... Tuberculosis (TB) is a very slow-progressing disease in humans, taking months for a person to develop symptoms after being infected with the bacteria Mycobacterium tuberculosis. ... this highlights an increasing need to understand what’s happening in the early stages, when TB bacteria first encounter the body’s defences in the air sacs in the lungs. ..."

From the abstract (emphasis added):

"Immunocompetent and experimentally accessible alveolar systems to study human respiratory diseases are lacking.

Here, we developed a single-donor human induced pluripotent stem cell-derived lung-on-chip (iLoC) containing type II and I alveolar epithelial cells, vascular endothelial cells, and macrophages in a microfluidic device that mimic lung three-dimensional mechanical stretching and air-liquid interface.

Imaging and single-cell RNA sequencing analysis revealed that the iLoC recapitulated cellular profiles present in the human distal lung.
Infection of the iLoC with the human pathogen Mycobacterium tuberculosis (Mtb) showed that both macrophages and epithelial cells were infected but not permissive to bacterial replication. Stochastically, large macrophage clusters containing necrotic macrophages supporting Mtb replication were observed. A genetically engineered autophagy-deficient iLoC revealed that after Mtb infection, macrophage necrosis was higher upon ATG14 deficiency without bacterial replication. Together, we report an autologous, genetically tractable human alveolar model to study lung diseases and therapies."

First breathing 'lung-on-chip' developed using genetically identical cells

Built to breathe: mini ‘lungs’ recreate individual response to infection (original news release) "Lung-on-chip device exposes earliest stages of tuberculosis infection, and opens doors to investigate diversity in disease progression and personalised treatment. "

Autologous human iPSC–derived alveolus-on-chip reveals early pathological events of Mycobacterium tuberculosis infection (open access)

Image of the lung-on-chip, with cell nuclei in blue, macrophage in magenta, endothelial cells in yellow and tight junctions between epithelial and endothelial cells in white.

Image of a lung-on-chip infected by Mycobacterium tuberculosis, with cell nuclei in blue, dead macrophage in magenta, tight junctions between epithelial and endothelial cells in yellow and TB bacteria in white.

Fig. 1. iPSC-derived iAT2 and iAT1s are differentiated in a lung-on-chip microfluidic device.

Fig. 5. The iLoC mimic early stages of infection with Mtb.