Lungs may be buried deep inside a person’s body, but they are also one of the most outward-facing organs. They endure a barrage of assaults carried in by the air we breathe, such as pollutants or pathogens such as SARS-CoV-2. This takes a toll, and it can be hard to find a new lung to transplant into a patient with a failing one.
A better solution would be to fix the damaged lung with a graft of healthy cells. In a pair of studies published in Cell Stem Cell, researchers showed that stem cells might make this a reality.1,2 A team of researchers led by Darrell Kotton, a stem cell biologist at Boston University, proposed a way to generate key lung progenitor cells from pluripotent stem cells and also how to help these cells put down lasting roots in the lung.
“It's a culmination of a long journey,” Kotton said. “With a lot of failed transplants along the way.”
This journey began in 2004, when Kotton’s lab first started engineering cells to graft into a damaged lung. They studied how lung cells develop naturally in an embryo and used what they learned to develop a strategy to mimic this in a lab dish.3 One challenge was the sheer number of unique cell types and functions in the lung. Kotton’s team ultimately decided that it would be best to find progenitor cells that already exist in the lung to help the organ regenerate.
The researchers decided to engineer cells that could rebuild two key parts of the lung: the airways, which carry oxygen through the lung, and the alveoli, where oxygen passes into the body. In each part of the lung, they identified a key progenitor cell and developed laboratory techniques to generate those progenitors from mouse pluripotent stem cells. But that alone was not enough. Lungs need to be coaxed to accept the graft, which has been a major hurdle in previous efforts.
“I think there’s been a failure in the lung field for many years trying to graft,” Kotton said. “No matter how good the cells that were transplanted, you can't just put them in the lungs and have them graft.”
Kotton’s team devised a way to use damaging chemicals to temporarily carve out space in mice’s lungs. This gave them a window of around five hours when the lung would be especially receptive to a graft. In that time, they transplanted their stem-cell derived lung cells into the mouse and then monitored the graft. They found that these stem-cell derived progenitors started producing cells that could carry out typical lung cell functions for more than six months after the transplant.
Transplants typically require immumosuppression to keep the body from attacking the foreign tissue. This can leave transplantees vulnerable to infections. Kotton’s stem-cell derived transplants did not require immunosuppression, making them a potentially safer alternative. Kotton also imagines the cells could be genetically edited before transplantation to turn them into cellular therapies for genetic diseases that damage the lungs, such as cystic fibrosis.
However, the technology is still far from being used in humans. One major limitation is the chemicals used to prepare the lung for the graft. Kotton said they cause too much damage to the lungs, so they would not be safe for humans.
Ed Morrisey, a lung biologist at the University of Pennsylvania, appreciates the authors’ transparency about the limitations of the method. He sees these studies as a promising proof-of-concept to help researchers better understand how to effectively heal a lung—for example, two progenitor cell types might not be enough to regenerate the complex structures of the lung, he said.
“There's still a lot of open questions, but there's a lot of things that this proof-of-concept can allow us to start thinking about that we couldn't [before],” Morrisey said.
References:
1. Ma L, et al. Airway stem cell reconstitution by the transplantation of primary or pluripotent stem cell-derived basal cells. Cell Stem Cell. 2023;30(9):1199-1216.
2. Herriges MJ, et al. Durable alveolar engraftment of PSC-derived lung epithelial cells into immunocompetent mice. Cell Stem Cell. 2023;30(9):1217-1234.
3. Ikonomou L, Kotton DN. Derivation of endodermal progenitors from pluripotent stem cells. J Cell Physiol. 2015;230(2):246–258.
