Reversing lung scarring with a shot of stem cells

When the world ground to a halt in 2020, news outlets regularly featured stories about how COVID-19 wreaked havoc on patients’ lungs. In millions of cases, an initial cough developed into full-blown pneumonia, which could scar lungs so badly that patients began to suffocate. But for many people who suffer from a buildup of scar tissue in their lungs, or pulmonary fibrosis, the root cause is unknown.

In cases of idiopathic pulmonary fibrosis (IPF), doctors like Peter Chen, a pulmonologist at Cedars-Sinai Medical Center, can prescribe antifibrotic drugs like nintedanib or pirfenidone to try slowing the development of scar tissue. “But their lungs continue to progress to fibrosis,” said Chen. “Those that qualify will oftentimes need a lung transplantation.”

Yair Reisner wears a jacket and tie against a gray background.

Yair Reisner looks for new ways to leverage stem cell transplantation to treat disease.

credit: Yair Reisner

When immunologist Yair Reisner at the University of Texas MD Anderson Cancer Center learned about IPF and its often bleak prognosis, he realized that his expertise in stem cell transplantation could help patients afflicted with this deadly disease. In a recent study in Science Advances, Reisner and his colleagues showed that lung stem cells harvested from healthy mice readily enter and colonize the lungs of mice with IPF-like symptoms via an injection into the bloodstream (1).

“The approach is extremely simple,” said Reisner. “So, we are very excited about it.”

To test their approach, Reisner’s team induced IPF-like symptoms in mice by administering biweekly doses of the toxic chemotherapy drug bleomycin to the mice for a month. They confirmed that lasting scar tissue developed in the animals’ lungs via CT scans and collagen staining. Additionally, fluorescent imaging of the lungs revealed that the bleomycin had eliminated the mice’s lung stem cells.

The stem cells’ absence was advantageous because it checked off a step for Reisner’s team. Often, doctors must condition patients to receive stem cell transplantations. For instance, many people in need of bone marrow transplants must first undergo chemotherapy or radiation to kill their own bone marrow cells. Without that step, the donor stem cells would have nowhere to set up shop.

“If you don’t make space, meaning open the niche of the stem cells, you will not see an outcome,” said Reisner.

The researchers injected a solution containing lung stem cells harvested from healthy mice into the tails of mice with diseased lungs, waited for two months, and then used fluorescent imaging to determine if the transplantation was successful. Not only were the donor stem cells present in the lungs, but they had successfully differentiated into a variety of important cell types necessary for healthy lung function. These changes coincided with improved lung function, as made evident by a forced exhalation test.

Still, the question about conditioning for stem cell transplantation lingered. Bleomycin is a toxic substance. It wasn’t clear if the drug happened to kill the mice’s stem cells as it scarred their lungs or if the depletion of lung stem cells was an integral part of the development of scar tissue.

Reisner was curious if removing host stem cells would be necessary in other models of IPF. He and his team decided to test their procedure again in mice with a mutation that made the animals susceptible to developing pulmonary fibrosis upon receiving regular doses of the medication tamoxifen, which doctors commonly prescribe to prevent breast cancer.

At this point, we think we have a very simple procedure that can be done everywhere.
- Yair Reisner, MD Anderson Cancer Center

Once again, the researchers observed that the progression of lung scarring went hand-in-hand with the loss of lung stem cells. In other words, mice that were already exhibiting IPF-like symptoms did not have their own stem cells to compete with transplants from healthy mice. When it came time to test their method of stem cell transplantation, Reisner and his team again saw success without having to perform any additional conditioning.

“In IPF, maybe we don’t need it,” said Reisner.

Chen, who was not involved in the study, was intrigued by the possibility that IPF on its own makes room in the lungs for donor stem cells, but he was skeptical. “I don’t know that’s necessarily the case,” he said. To be convinced, he would need to see data from human patients with IPF showing that their scarred lungs have no stem cells that could compete with a donor’s.

If it’s up to Reisner, those answers will come sooner than later. He’s eager to give his procedure a go in human patients, although he knows the process will take years. Even if Reisner and his colleagues can move forward with human trials, Chen wonders if their procedure would actually bring fundamental change for patients with IPF. He noted that Reisner’s team had to use an entire donor lung to harvest stem cells for each recipient mouse.

“What’s the advantage of this versus just transplanting the lung?” asked Chen.

At the moment, Reisner thinks this procedure would allow doctors to use lungs that they otherwise would reject for transplantation. “It will have to be, initially, from cadaveric lungs that are not used,” he said.

If the procedure proves successful in humans, Reisner envisions a world where banks store and grow harvested lung cells, enabling one donor lung to treat multiple patients. “But at this point, we think we have a very simple procedure that can be done everywhere,” said Reisner.