Tissue engineers have made amazing progress when it comes to using stem cells to build tissues such as blood vessels, which have relatively simple tubular shape. In fact, a late stage CIRM-funded clinical trial run by Humacyte is testing an engineered vein to improve dialysis treatment for people with kidney disease. Building a lung that works properly, on the other hand, has proven elusive due in no small part to its extremely intricate structure. But in a Science Advances report published yesterday, Columbia University bioengineers describe a potentially breakthrough method for building a functional lung in the lab.

Building a better lung that removes and repopulates lung cells without hurting blood vessels. Figure courtesy of N. Valerio Dorrello and Gordana Vunjak-Novakovic, Columbia University.

Lung disease tends to not get as much attention as other deadly diseases like cancer and heart failure. Yet it’s the world’s third leading cause of death with 400,000 deaths per year in just the United States. The only true treatment is a very drastic one: a lung transplant. This option is not very attractive even to those with severe disease because it’s a very expensive procedure that only has a 10-20% survival rate after 10 years. On top of that, donor lungs are in very short supply. So, clinicians and their patients are in desperate need for other approaches.

Tissue engineering approaches to building a lung face many challenges due to the organ’s complex structure. How complex, you ask? Science writer and scientist, Shelly Fan, uses a great analogy to describe it in her Singularity Hub article about this study:

“The lung is a real jungle: at the microscopic level, the tree-like airways contain alveoli, tiny bubble-like structures where the lungs exchange gas with our blood. Both arteries and veins enwrap the alveoli like two sets of mesh pockets.”

Now, one approach to building an organ is to start from scratch by manufacturing a synthetic scaffold resembling the shape of the organ and then seeding it with stem cells or other precursor cells. But because of this complicated microscopic jungle, bioengineers have steered clear of this path. Instead, the Columbia team has generated a natural scaffold by removing the cells from rat lungs using detergents. What’s left behind is a lung “skeleton” of proteins and molecules called the extracellular matrix that’s devoid of cells.

Building a better lung that removes and repopulates lung cells without hurting blood vessels. Figure courtesy of N. Valerio Dorrello and Gordana Vunjak-Novakovic, Columbia University.

In previous experiments using rat lungs, the team stripped out the lung cells, called epithelial cells, which are the type typically damaged in lung disease. Their method also removed the blood vessel cells, called endothelial cells, which make up the vascular system that is key to taking up the oxygen inhaled into the lungs. While repopulating the functional epithelial cells has been achieved, restoring the blood vessels is another story as mentioned in a university press release:

“An intact vascular network—missing in these scaffolds—is critical not only for maintaining the blood-gas barrier and allowing for proper graft function, but also for supporting the cells introduced to regenerate the lung. This has proved to be a daunting challenge.”

So, the current study attempted to only clear out the lung epithelial cells without disturbing the blood vessels to see if they would have better results. This approach makes sense on another level when envisioning future clinical applications: the therapy would be less complex if you only had to remove the diseased cells, which typically are the lung epithelial cells.

The researchers devised a cell removal method that was specific to the airways so that only epithelial cells would be cleared away. A battery of tests showed that, that although the lungs lost much of their ability to inflate and expand, the blood system remained intact after the procedure. The team then introduced either human epithelial cells or human induced pluripotent stem cell-derived epithelial cells into the scaffold. Within a day, they watched as the cells began to repopulate the lung in the correct areas. Follow-up experiments showed that the addition of new epithelial cells restored a good portion of the lungs expansion abilities.

Lead author, Dr. N. Valerio Dorrello, gave a big picture perspective on how this proof-of-concept study could one day help those who suffer from lung disease:

Nicolino Valerio Dorrello, MD

“Every day, I see children in intensive care with severe lung disease who depend on mechanical ventilation support. The approach we established could lead to entirely new treatment modalities for these patients, designed to regenerate lungs by treating their injured epithelium.”