Inhaling secretions produced by lung stem cells could be therapeutically beneficial for those with idiopathic pulmonary fibrosis (IPF), a preclinical study has suggested.
The study, “Inhalation of lung spheroid cell secretome and exosomes promotes lung repair in pulmonary fibrosis,” was published in the journal Nature Communications.
IPF is characterized by tissue scarring, called fibrosis, in the lungs. Some evidence suggests that stem cells in the lungs could help in reducing such fibrosis.
Indeed, the same team of researchers behind this new study had previously developed a method to harvest and culture large numbers of lung stem cells using three-dimensional spheroids. Their research showed that lung spheroid cells could be therapeutic in a mouse model of pulmonary fibrosis (PF).
Spheroids are round aggregates, or clusters of cells composed by lung stem cells — found in the clump’s center — and support cells, also known as stromal cells. Lung spheroid cells (LSCs) are mixtures of these two cell populations.
“Although stem cells have beneficial effects, their clinical applications face many challenges, including extensive labor, high cost, and safety concerns,” the researchers said.
One possible way to get around these challenges would be to use the substances these cells produce and release, rather than the cells themselves.
“The mixture of cells in LSCs recreates the stem cells’ natural microenvironment — known as the stem cell niche — where cells secrete exosomes to communicate with each other just as they would inside your body,” Ke Cheng, PhD, a professor of regenerative medicine at North Carolina State University and co-author of the study, said in a press release.
“LSCs secrete many beneficial proteins and growth factors known collectively as ‘secretome’ — exosomes and soluble proteins which can reproduce the regenerative microenvironment of the cells themselves,” Cheng said. “In this work we took it one step further and tested the secretome and exosomes from our spheroid-produced stem cells against two models of pulmonary fibrosis.”
First Cheng and his team treated mice with bleomycin, an anti-cancer drug, to trigger the onset of PF. Then, once tissue scarring set in, they started treating the animals with LSC secretome (LSC-sec), which was turned to mist with a nebulizer and inhaled.
The results showed that LSC-sec treatment reduced fibrosis, as measured by the Ashcroft score, by nearly 50% compared with sick mice treated with a saline solution. Examinations of the animals’ lung tissues further suggested that LSC-sec promoted the repair of airways and blood vessels in scarred lungs.
LSC-sec treatment also produced statistically significant, though less pronounced, effects in a second mouse model of pulmonary fibrosis. In these animals, the disease was induced by the inhalation of fine silica particles, essentially sand. The Ashcroft score in these animals was reduced by 26%.
Importantly, in both models, LSC-sec treatment was more effective compared with treatment with the secretome, or substance produced by another kind of stem cells, called mesenchymal stem cells (MSCs). MSCs are adult stem cells; the substances produced by them are known as MSC-sec. Their use decreased the Ashcroft score by 32.4% in the bleomycin model, and by 16.9% in the silica model.
“The field of regenerative medicine utilizes many types of stem cells for research and clinical applications, but mesenchymal stem cells remain the most widely used,” the researchers said.
“Our observations in both Bleo and silica models demonstrated that while MSC-Sec inhalation therapy was effective in treating pulmonary fibrosis, LSC-Sec was superior to MSC-Sec in all measures,” they said.
Similar results were found in a rat model of bleomycin-induced PF, with LSC-sec treatment significantly reducing the animals’ Ashcroft scores.
Moreover, investigators found that inhaling LSC exosomes — membrane-bound bundles of cellular contents that are released by cells for communication — also was effective in this model, though to a lesser extent compared with treatment with the full secretome.
In the rat model, LSC-sec treatment also led to significant improvements in the animals’ lung function, which could not be assessed in mice. Additionally, analysis of other organs in the rats — including the kidney and heart — showed no apparent signs of toxicity associated with LSC-sec treatment.
Overall, the findings of this study suggest that LSC-sec inhalation could be therapeutic for those with IPF.
“Hopefully we are taking our first steps toward an efficient, non-invasive and cost-effective way to repair damaged lungs,” Cheng said, adding that these findings could have implications beyond IPF.
“Given the therapy’s effectiveness in multiple models of lung fibrosis and inflammation, we are planning to expand the test into more pulmonary diseases, including chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), and pulmonary hypertension (PH),” Cheng added.
“The finding that products released by lung stem cells can be just as efficacious, if not more so, than the stem cells themselves in treating pulmonary fibrosis can be a major finding that can have implications in many other diseases where stem cell therapy is being developed,” said Kenneth Adler, MD, a professor at NC State and co-author of the study.
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