SHANGHAI — Researchers from Shanghai Jiao Tong University School of Medicine published findings on June 11, 2026, in the journal Bone Research, detailing the role of p16 INK4a+ mesenchymal cells in tendon repair. The study investigated the epigenetic regulation involving JMJD3 and H3K27me3 in this process.

The research team, led by Professor Shen Liu from the Department of Orthopedics at Shanghai Sixth People's Hospital, utilized mice with Achilles tendon injuries to observe p16 INK4a+ cells. They tracked these cells over time and analyzed cell types in injured tendons through single-cell RNA sequencing. The number of p16 INK4a+ cells, which are rare in healthy tendons, increased markedly within damaged tendon tissue approximately seven days post-injury in the mouse model.

Further experiments showed that removing p16 INK4a+ cells from injured tissue in the mouse model resulted in poorer healing outcomes, producing weaker and less mature tendons. These tendons displayed disorganization of collagen fibers, a reduced number of repair cells, and heightened inflammation at the injury site. The study identified p16 INK4a+ cells as mesenchymal cells, a type of connective tissue cell known to produce high levels of collagen and factors that promote new blood vessel and nerve formation.

The researchers found that p16 INK4a+ mesenchymal cells in injured tendons contained elevated levels of the protein JMJD3 and low levels of the epigenetic mark H3K27me3. JMJD3 removes the H3K27me3 epigenetic mark, which acts as a suppressor of repair genes. When JMJD3 was removed, overall tissue repair in the mouse model was impaired.

In cell culture, researchers created tendon-injury-like p16-positive cells using the drug doxorubicin. Blocking JMJD3 with the drug GSK-J4 in this model increased H3K27me3 levels, decreased collagen production, and worsened healing. Conversely, blocking the enzyme EZH2, which produces H3K27me3, lowered H3K27me3 levels. This action improved collagen organization, increased tendon-specific repair markers, and enhanced the mechanical strength of repaired tendons.

Professor Shen Liu stated, "Because tendons rarely heal well even with surgery, we were curious to know if p16 INK4a+ cells could help in the repair of injured tendons as had been demonstrated in skin and lungs." The findings identify a cellular mechanism that contributes to tendon healing, an area where current treatment options frequently result in incomplete recovery. Tendon injuries often present challenges due to their slow healing processes and the limited efficacy of surgical interventions. Understanding how p16 INK4a+ mesenchymal cells and their epigenetic regulation via JMJD3 and H3K27me3 contribute to repair could provide new targets for therapeutic development. The study's detailed analysis of cellular and molecular changes during tendon repair in a mouse model offers insights into potential biological pathways that could be manipulated to improve healing outcomes in the future.