How Stem Cell Therapy Works to Ease COPD Described in Study
Treatment with human mesenchymal stem cells (MSCs) results in a strong, but temporary, reduction in pro-inflammatory molecules involved in chronic obstructive pulmonary disease (COPD), according to data from a Phase 1 clinical trial involving nine COPD patients.
Notably, molecules directly produced by MSCs were identified as potential drivers of these anti-inflammatory effects.
These findings help in understanding how MSC-based therapies may benefit people, and suggest “that frequent, perhaps weekly doses, may be important to achieve clinical benefit in COPD patients,” Yuben P. Moodley, MD, PhD, the study’s senior author and head of the Cell Biology Unit at the Institute for Respiratory Health, in Australia, said in a press release.
“The insights gained from this study warrant further investigation of MSCs and/or their secreted [produced] factors as a novel therapeutic intervention in chronic airways diseases,” added Moodley, who is also a consultant respiratory physician at Fiona Stanley Hospital and an associate professor of respiratory medicine at the University of Western Australia.
The study, “Transcriptional profiling of circulating mononuclear cells from patients with chronic obstructive pulmonary disease receiving mesenchymal stromal cell infusions,” was published in the journal STEM CELLS Translational Medicine.
COPD is characterized by excessive and sustained airway inflammation, and oxidative stress that lead to permanent lung damage. Oxidative stress is a type of cellular damage resulting from an imbalance between the production of harmful oxidant molecules and the cells’ ability to clear them with antioxidants.
MSCs have gained increasing interest as a potential COPD treatment, due to their ability to mature into many other cell types and produce molecules with immunomodulatory, anti-inflammatory, and regenerative properties.
While MSCs were shown in rodent models to effectively lessen inflammation and emphysema, a severe form of COPD in which the lungs’ tiny air sacs become damaged, “these findings have translated poorly in human studies,” the researchers wrote.
The reasons for this lack of efficacy in clinical trials are unclear, which is further “underscored by a lack of mechanistic studies in humans,” the team added.
To address this, Moodley and his colleagues characterized the immunological changes occurring in blood cells from nine adults with stable, moderate to severe COPD, who were treated with MSCs in a Phase 1 trial (ACTRN12614000731695).
Participants, recruited at the Royal Perth Hospital, in Australia, received two into-the-vein infusions of two million MSCs per kilogram of body weight, one week apart. MSCs were collected from the bone marrow of two different donors; eight patients received cells from a 28-year-old woman, and one patient from a 20-year-old man.
Patients were a median age of 70, and all were former smokers.
Previous trial data showed that MSC-based treatment was well tolerated and led to short-term reductions in the levels of systemic inflammation and oxidative stress biomarkers.
In the current study, researchers analyzed the gene activity profiles of the patients’ blood cells before treatment, and in the first week following infusion (at one hour, and one, two, and seven days after the first infusion; and one hour after the second infusion).
MSC-based treatment significantly suppressed inflammatory signaling pathways, reducing the levels of pro-inflammatory molecules known to drive COPD, such as IL-1 beta and IL-8, results showed.
These anti-inflammatory effects were more pronounced around one day post-infusion, fading away by the seventh day, suggesting that frequent, once weekly dosing may be important in achieving clinical benefit.
These results are consistent with those reported in a “recent study in patients with septic shock receiving MSC infusions, where inflammatory levels were most prominently reduced around 12 to 24 hours after infusion, then reverted to baseline [initial] levels in the subsequent days,” Moodley said.
The observed short-time effects “are likely a consequence of the rapid breakdown of MSCs following intravenous [into-the-vein] infusion,” the researchers wrote.
Researchers also found that soluble factors produced by MSCs may be responsible for these anti-inflammatory effects, as similar results were obtained when patients’ blood cells collected before treatment were grown in a medium where MSCs had previously been grown, or in patients’ post-infusion blood.
Further analysis on MSC-grown media and post-infusion blood revealed the presence of several soluble immunoregulatory factors, such as TNFR1, TGF-beta 1, and microRNAs inside tiny vesicles. Of note, microRNAs are small RNA molecules that help regulate the activity of different genes within cells.
These findings “provide novel insights into the mechanisms of MSC-mediated systemic immunomodulation, as these short-term dynamics have not previously been described in human studies,” the researchers wrote.
They also “strengthen the hypothesis that therapies using MSCs and their secreted products may be beneficial to patients with COPD,” and help guide further research on these therapeutic approaches.
Anthony Atala, MD, the editor-in-chief of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine, said that these findings “are interesting and provide novel insights into how stem cells work to alleviate symptoms associated with chronic airways disease in patients.”
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