After muscle injury, muscle stem cells must coordinate with immune cells in the inflamed tissue to ensure efficient repair.
In damaged muscle, stem cells must work together with immune cells to complete the repair process, yet how these cells coordinate to ensure the efficient removal of dead tissue before making new muscle fibers has remained unknown.
When muscles get damaged, it is important for immune cells to quickly enter the tissue and remove the damage before stem cells begin repair , it is like immune cells maintain the stem cells in a resting state while they finish the cleanup job. After about 40 hours, once the cleanup job is finished, an internal alarm goes off in the muscle stem cells that allows them to wake up and start repair.
Dr. Jeffrey Dilworth, senior scientist at The Ottawa Hospital and professor at the University of Ottawa and his team identified hyaluronic acid as the key ingredient in this internal alarm clock that tells muscle stem cells when to wake up.
When muscle damage occurs, stem cells start producing and coating themselves with hyaluronic acid. Once the coating gets thick enough, it blocks the sleep signal from the immune cells and causes the muscle stem cells to wake up.
They identified an essential role for the epigenetic enzyme KDM6B/JMJD3 in establishing the communication between muscle stem cells and infiltrating immune cells during muscle repair on mouse and human tissue models. They found that, in response to injury, removal of the transcriptionally repressive histone H3K27me3 modification by KDM6B/JMJD3 allows muscle stem cells to produce hyaluronic acid that is then incorporated into the extracellular matrix. This remodeling of the extracellular matrix allows the muscle stem cell to receive signals from the infiltrating immune cells that initiate regeneration.
The authors note that the regenerative effect of hyaluronic acid seems to depend on it being produced by the muscle stem cells. The team is currently examining if drugs that modify the epigenetics of muscle stem cells could be used to increase their production of hyaluronic acid.
Kiran Nakka, Sarah Hachmer, Zeinab Mokhtari, Radmila Kovac, Hina Bandukwala, Clara Bernard, Yuefeng Li, Guojia Xie, Chengyu Liu, Magid Fallahi, Lynn A. Megeney, Julien Gondin, Bénédicte Chazaud, Marjorie Brand, Xiaohui Zha, Kai Ge, F. Jeffrey Dilworth (August 4, 2022). JMJD3 activated hyaluronan synthesis drives muscle regeneration in an inflammatory environment. Science: https://www.science.org/doi/10.1126/science.abm9735