Scientists at Trinity College Dublin have discovered that electrically stimulating macrophages can “reprogram” them in such a way to reduce inflammation and encourage faster, more effective healing in disease and injury. In vitro studies using human macrophages from healthy donors showed that electrical stimulation promotes an anti-inflammatory, pro-regenerative phenotype, decreases inflammatory macrophage marker expression, and enhances expression of angiogenic genes. Further tests showed the ability of electrically stimulated macrophages to promote angiogenic tube formation in human umbilical vein endothelial cells (HUVECs), and trigger mesenchymal stem cell (MSC) migration in a wound scratch model.
This breakthrough uncovers a potentially powerful new therapeutic option, with further work ongoing to delineate the specifics. “We are really excited by the findings,” commented said Sinead O’Rourke, PhD, Research Fellow in Trinity’s School of Biochemistry and Immunology. “Not only does this study show for the first time that electrical stimulation can shift human macrophages to suppress inflammation, we have also demonstrated increased ability of macrophages to repair tissue, supporting electrical stimulation as an exciting new therapy to boost the body’s own repair processes in a huge range of different injury and disease situations.”
O’Rourke is first author of the team’s published paper in Cell Reports Physical Science, titled “Electromodulation of human monocyte-derived macrophages drives a regenerative phenotype and impedes inflammation,” in which the author stated that their collective findings “…endorse electrical stimulation as a viable therapeutic strategy for the modulation of macrophages across multiple injury and defense microenvironments.”
The immune system plays a pivotal role in tissue healing, with immune cells dictating host responses at sites of injury, and coordinating the activity of tissue-specific cell populations, the authors wrote. “As such, modulation of the immune response has become a focus in standard clinical medicine and tissue engineering to combat pathophysiological conditions associated with aberrant tissue repair and improve tissue regeneration.”
Macrophages are an innate immune cell with several high-profile roles in our immune system, playing a role in both the early and late stages of tissue repair and damage. They patrol around the body, surveying for pathogens, as well as disposing of dead and damaged cells, and stimulating other immune cells when and where they are needed.
Peripheral monocytes that are recruited to the site of tissue damage soon after injury differentiate into pro-inflammatory macrophages (commonly known as classically activated macrophages), which clear cellular debris and break down the extracellular matrix in order to make way for healthy tissue remodeling, the team further explained. As time progresses, these pro-inflammatory macrophages adopt an anti-inflammatory, regenerative phenotype (known as “alternatively activated”) to facilitate the later stages of tissue healing. These alternatively activated macrophages dampen the inflammatory response associated with initial injury and promote healing-associated processes such as angiogenesis and matrix deposition.
However, their actions can also drive local inflammation in the body, which can sometimes get out of control and become problematic, causing more damage to the body than repair. This is present in lots of different diseases, highlighting the need to regulate macrophages for improved patient outcomes. “Failure to undergo this phenotypic switch results in a persistent chronic inflammatory response and maladaptive repair processes, ultimately leading to pathological fibrosis and eventual organ failure and death,” the investigators stated. “Consequentially, considerable focus has been directed toward advancing strategies that modulate macrophage phenotype in order to inhibit chronic inflammation and promote more effective tissue repair/regeneration.”
“We have known for a very long time that the immune system is vital for repairing damage in our body and that macrophages play a central role in fighting infection and guiding tissue repair,” said O’Rourke. “As a result, many scientists are exploring ways to ‘reprogramme’ macrophages to encourage faster, more effective healing in disease and to limit the unwanted side-effects that come with overly aggressive inflammation.”
Electrical stimulation has the potential to regulate cell function during wound healing and regeneration, they pointed out, but there have been limited studies investigating the effects of electrical stimulation on macrophages, particularly primary human cells—“the reparative potential of electrically stimulated primary human macrophages has not been extensively characterized,”—which has limited the potential for clinical translation.
“…while there is growing evidence that electrical stimulation may help control how different cells behave during wound healing, very little was known about how it affects human macrophages prior to this work,” O’Rourke added.
For their newly reported study the team worked with human macrophages isolated from heathy donor blood samples provided via the Irish Blood Transfusion Board, St James’s Hospital. They stimulated the cells using a custom bioreactor to apply electrical currents.
The results of their tests showed that electrical stimulation caused the macrophages to shift into an anti-inflammatory state that supports faster tissue repair. There was in addition a decrease in inflammatory marker activity, an increase in expression of genes that promote the formation of new blood vessels (associated with tissue repair), and an increase in stem cell recruitment into wounds, which is also associated with tissue repair.
“Our study demonstrates the lasting regenerative effects of electrical stimulation on primary human macrophages, with anti-inflammatory and regenerative marker expression sustained at 72 h post-stimulation,” the team noted. Such insight, they suggest, is of important physiological and clinical relevance that hasn’t previously been reported in the literature. “Demonstrating that electrical stimulation can modulate macrophage function toward a regenerative phenotype during this key period supports the translational relevance of our findings.”
“We are really excited by the findings,” said O’Rourke. “Not only does this study show for the first time that electrical stimulation can shift human macrophages to suppress inflammation, we have also demonstrated increased ability of macrophages to repair tissue, supporting electrical stimulation as an exciting new therapy to boost the body’s own repair processes in a huge range of different injury and disease situations.”
The interdisciplinary team was led by Trinity investigators, Professor Aisling Dunne, PhD, at the School of Biochemistry and Immunology, and corresponding author Professor Michael Monaghan, PhD, at the School of Engineering. The researchers suggest the findings are especially significant given that the work was performed with human blood cells, indicating potential effectiveness for real patients, and that electrical stimulation could be relatively safe and easy in the scheme of therapeutic options, and applicable to a wide range of scenarios.
Monaghan stated, “Among the future steps are to explore more advanced regimes of electrical stimulation to generate more precise and prolonged effects on inflammatory cells and to explore new materials and modalities of delivering electric fields. This concept has yielded compelling effects in vitro and has huge potential in a wide range of inflammatory diseases.”
In their paper the team suggested that “Future investigations to elucidate the mechanisms by which this occurs in macrophages would be of significant benefit, not only to further the work of this study but, furthermore, to identify potent pharmaceutical targets for macrophage modulation…Validation of our in vitro findings in an appropriate in vivo model would also represent an important next step to further our work in a pre-clinical setting.”