Common types of tissue damage, such as external injuries from bumps and bruises, surgical wounds, and muscle degeneration due to aging, are an inevitable part of life. The speed at which wounds heal and tissues regenerate has a direct impact on overall health. Inflammation plays a vital role in this repair process, with some clinical studies suggesting that using anti-inflammatory drugs too soon after surgery may actually slow down wound healing. This underscores the importance of understanding how early inflammation contributes to later stages of tissue rebuilding.

A breakthrough study by Professor WANG Di’s team at Zhejiang University’s School of Medicine sheds new light on this process. The researchers found that when human tissue is damaged, macrophages—critical immune cells—will be activated into a hyperactive state. In this state, the cells create pores on their membranes using a protein called GSDMD, allowing them to release specific lipid molecules that promote tissue repair. The findings, published on September 11 in Nature in an article titled “Gasdermin D-mediated metabolic crosstalk promotes tissue repair”, offer new insights into how the body heals itself.

The potential of “hyperactivation”

Macrophages, which play a central role in the body’s inflammatory response, are present throughout the human body. A critical player within these cells is the protein GSDMD, which has long been recognized for its role in defending against pathogens and inflammatory diseases by triggering inflammation. Previous studies suggested that when the body is under threat, GSDMD is activated to form pores in cell membranes, leading to a type of cell death known as pyroptosis.

However, a breakthrough discovery by the research team revealed that during tissue repair, these GSDMD pores in macrophages don’t necessarily result in cell death. Instead, the macrophages enter a “hyperactive” state, retaining critical functions that help the body heal.

The big question: how do these hyperactive macrophages contribute to tissue repair?

The researchers postulated that these macrophages might secrete bioactive metabolites and other factors through GSDMD pores to influence adjacent cells or shape the surrounding tissue environment.

To their surprise, they found that in addition to releasing inflammatory signals, hyperactive macrophages also secrete a specific lipid metabolite called 11,12-EET through GSDMD pores. This molecule, found in both lab-grown macrophages and injured muscle tissue, plays a crucial role in the healing process, actively boosting the repair of damaged tissue.

The miraculous “repair agent”

Tissue repair hinges on the ability of stem cells to proliferate and differentiate. However, stem cells don’t work alone; they need the help of surrounding cells to thrive. Imagine stem cells as seeds with unlimited potential. For these seeds to sprout and grow, they need nourishments from the “soil,” or the microenvironment of the damaged tissue.

As essential players in this microenvironment, macrophages fulfill multiple roles by releasing pro- and anti-inflammatory mediators, growth factors, and other bioactive molecules. However, the metabolic communication between macrophages and other types of cells—and how these exchanges help coordinate tissue repair—have largely remained enigmatic.

To address this, the researchers zeroed in on a key factor: 11,12-EET. They employed a two-pronged approach, supplementing 11,12-EET externally and knocking out its degrading enzyme in macrophages of mice to boost its endogenous level. Both approaches provided compelling evidence that 11,12-EET is crucial for activating and proliferating muscle stem cells.

More importantly, the team found that the regenerative potential of 11,12-EET depends on GSDMD creating effective metabolic communication channels between macrophages and muscle stem cells. This discovery opens the door to a new understanding of how macrophages and stem cells interact, and sheds fresh light on the critical function of membrane pores in tissue repair.

The versatile role of 11,12-EET

One of the biggest challenges in tissue repair is the low concentration of regenerative factors in the damaged areas, making it difficult for the body to trigger a swift and efficient healing process. This is where the lipid molecule 11,12-EET comes in, playing a critical role in amplifying the body’s repair signals.

By studying the behavior of primary muscle stem cells, both with and without exposure to 11,12-EET, the researchers discovered that the molecule helps gather growth factors in the damaged tissue. This leads to a more favorable environment for healing, accelerating the regeneration process.

Given 11,12-EET’s ability to activate stem cells, could this function have broader applications?

The team tested its therapeutic potential on models of muscle, corneal, and skin injuries. The results were impressive—11,12-EET exhibited broad tissue-repair capabilities. What’s more, it even helped aging mice regain muscle vitality by increasing their muscle stem cell reserves and stimulating the proliferation of human muscle stem cells.

“This offers strong support for the clinical use of 11,12-EET,” said CHI Zhexu, the first author of the paper. “It opens up new vistas for treating wounds, tissue damage, and muscle degeneration in aging patients.”