Melatonin Primed Stem Cells Reduce Lung Inflammatory Cells in Asthma Mouse Model

Professor Dong-Myung Shin’s Research Team at Asan Medical Center Publishes in Top Tier Chemical Engineering Journal

▲ (From left) Professor Dong-Myung Shin of the Department of Cell and Genetic Engineering at the Asan Institute for Life Sciences, Asan Medical Center, together with Professor Sang-Yeob Kim of the Convergence Medicine Research Center and Professor Eui Man Jeong of the College of Pharmacy at Jeju National University

Allergic asthma is characterized by airway inflammation and swelling, leading to shortness of breath and severe coughing. As there is still no definitive treatment, many patients experience a significant decline in quality of life. In this context, a recent animal study by a Korean research team has demonstrated that stem cells treated with melatonin are effective in alleviating asthma, drawing attention as a potential new therapeutic approach.

A research team led by Professor Dong-Myung Shin of the Department of Cell and Genetic Engineering at the Asan Institute for Life Sciences, Asan Medical Center, together with Professor Sang-Yeob Kim of the Convergence Medicine Research Center and Professor Eui Man Jeong of the College of Pharmacy at Jeju National University, found that administering melatonin primed mesenchymal stem cells to mice with asthma led to a marked reduction in the number of inflammatory cells in the lungs.

Priming is a technique that enhances the function of stem cells by exposing them in advance to specific substances. Melatonin primed stem cells refer to stem cells that have been treated with a melatonin solution, which has antioxidant and anti-inflammatory properties, thereby strengthening the cells’ therapeutic functions.

This study is significant in that it elucidated the mechanism by which melatonin enhances the anti-inflammatory and immunoregulatory functions of mesenchymal stem cells and, for the first time, demonstrated that melatonin primed mesenchymal stem cells produce a tangible inflammation reducing effect in an asthma animal model.

The findings were recently published online in the ‘Chemical Engineering Journal’, a top tier journal ranked within the top 3 percent in the field of chemical engineering, with an impact factor of 13.2.

To support the in vivo findings, the research team investigated the mechanism by which melatonin enhances the functional capacity of mesenchymal stem cells. In particular, they examined how melatonin protects mesenchymal stem cells from cellular damage and death caused by ferroptosis stress, a process in which excessive iron activity leads to lipid oxidation and subsequent cell injury, by monitoring glutathione dynamics. Glutathione is a major antioxidant in the human body, and sufficient intracellular glutathione levels enable cells to withstand ferroptosis related stress.

To elucidate the mechanism by which melatonin improves glutathione dynamics, the research team focused on the CREB1 NRF2 pathway, which is regarded as one of the key mechanisms underlying the functional enhancement of mesenchymal stem cells. This pathway is known as a signaling circuit that increases glutathione, a cytoprotective molecule that plays a central role in cellular defense.

Using Förster resonance energy transfer (FRET) technology, the research team precisely monitored real time changes in protein activity within stem cells. The results showed that protein kinase A, which functions as a molecular switch for CREB1, was more strongly activated in melatonin primed mesenchymal stem cells. This activation in turn stimulated the CREB1-NRF2 pathway, leading to enhanced maintenance of glutathione levels within the cells.

Through additional transcriptome analysis, the team identified activation of the JAK-STAT pathway as another key mechanism of melatonin action and demonstrated that an increase in PD-L1, a protein critical to immune checkpoint regulation, ultimately leads to enhanced immunomodulatory function of melatonin primed mesenchymal stem cells.

In other words, melatonin was shown to activate the CREB1-NRF2 pathway, promoting cellular protection, antioxidant activity, and glutathione maintenance, while simultaneously activating the JAK-STAT pathway to strengthen immune responses and the immunoregulatory capacity of stem cells.

Meanwhile, co corresponding author Professor Keunhong Jeong of the Korea Military Academy automated the counting of immune cells in bronchoalveolar lavage fluid using machine learning, thereby reducing inter researcher variability in immune cell analysis and enabling more efficient and reliable research.

Professor Dong-Myung Shin of the Department of Cell and Genetic Engineering at the Asan Institute for Life Sciences, Asan Medical Center, said, “This study goes beyond simply demonstrating the antioxidant effects of melatonin. Its significance lies in identifying melatonin as the most effective candidate substance for enhancing the function of mesenchymal stem cells, which are recognized as safe materials listed in international pharmacopeias.”

He added, “By applying real time redox indicators and FRET technology that allow quantitative prediction of the therapeutic efficacy of mesenchymal stem cells, this research presents an important clue for the development of high performance stem cell therapeutics suitable for clinical application.”

This research was conducted with support from the Ministry of Science and ICT and the National Research Foundation of Korea through the Mid-Career Researcher Program, the STEAM Research Program for Future Promising Convergence Technology Pioneers, and the Pan-Ministry Regenerative Medicine Technology Development Program.