Tendon injuries are very common, but they often heal with scar tissue, making them less flexible and more susceptible to future injuries. Developing effective therapeutic tools requires better insight into the biological mechanisms that promote stronger and more complete tendon repair. A group of cells that are attracting attention are cells that express a protein called p16INK4a. Cells that produce this protein are called p16INK4a+, and it has traditionally been thought to be non-beneficial because it is associated with aging, cellular stress, and a process called senescence, in which cells stop dividing. However, some recent studies in other tissues suggest that these cells may help repair damaged tissue.
In a recent study published online on June 11, 2026, in the journal bone research, Chinese researchers led by Professor Shen Liu, Department of Orthopedics, Shanghai Sixth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, investigated whether p16INK4a+ cells play a role in tendon injury. “Tendons rarely heal well even after surgery, so we wanted to know whether p16INK4a+ cells could help repair damaged tendons, as has been demonstrated in the skin and lungs.” says Professor Ryu. Using mice with Achilles tendon injuries, they tracked p16INK4a+ cells over time and analyzed the types of cells present in the injured tendon at different time points using a technique called single-cell RNA sequencing that measures gene activity in individual cells.
Approximately 7 days after tendon injury, the number of p16INK4a+ cells increased significantly within the injured tissue. In healthy, uninjured tendons, such cells are extremely rare. Removing them from injured tissue reduces healing ability, weakens the tendon, and reduces maturation. Collagen fibers, the main protein that makes up tendons, were disorganized, repair cells were reduced, and inflammation increased around the injury site. This suggests that p16INK4a+ cells contribute to repair rather than causing damage. Further research revealed that p16INK4a+ cells are actually mesenchymal cells, a type of connective tissue cell. They produce high levels of collagen and factors that promote the formation of new blood vessels and nerves, which are important for normal tendon function.
These cells were thought to be associated with aging and not beneficial, so researchers investigated how these cells switch into “repair mode.” They thought the answer might involve “epigenetics,” the “switches” cells use to turn genes on and off. They focused on a protein called “JMJD3,” which removes the “gene-off” epigenetic mark “H3K27me3” on repair genes. In this study, we found that p16INK4a+ mesenchymal cells in injured tendons contained high levels of JMJD3 and low levels of H3K27me3. They concluded that H3K27me3 suppresses the activity of normal tendon repair genes. Upon injury, JMJD3 removes this repressive mark, allowing gene expression. Furthermore, when JMJD3 was removed, repair throughout the tissue was impaired.
To add further evidence, the researchers created tendon injury-like p16-positive cells in culture using a drug called doxorubicin. They then blocked JMJD3 with a drug called GSK-J4. This increased H3K27me3, an off-switch for repair genes, decreased collagen production and worsened healing. Then they performed the opposite experiment. The enzyme EZH2, which produces H3K27me3, was blocked and H3K27me3 was reduced. This improved collagen organization, increased tendon-specific repair markers, and enhanced mechanical strength of repaired tendons.
In conclusion, these experiments provided a new perspective on p16INK4a+ cells, which were thought to be noninformative.
We did not want to compromise on the quality of the evidence. This research could lead to major changes in how we understand and approach tendon repair in the future. ”
Professor Xiaonan Liu, first author
It showed how epigenetic modifications can drive cells from “senescence mode” to “repair mode” and regenerate strong tendons with organized collagen structures and healthy blood vessel and nerve growth. In the future, targeting epigenetic pathways will be a promising strategy to improve tendon healing.
sauce:
Shanghai Jiao Tong University School of Medicine
Reference magazines:
Epigenetic reprogramming of p16INK4a-positive cells by JMD33 promotes tendon regeneration. bone research. DOI: 10.1038/s41413-026-00537-1
