A recent study published online on June 11, 2026, in the journal Bone Research investigates how certain aging cells contribute to tendon healing. Researchers from China, led by Professor Shen Liu from the Department of Orthopedics at Shanghai Sixth People's Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, examined whether p16INK4a+ cells play a role in repairing injured tendons.
Tendon injuries often heal with scar tissue that is less flexible and more susceptible to future injury. The research team used mice with Achilles tendon injuries and tracked p16INK4a+ cells over time. They analyzed cell types present at various stages after injury using single-cell RNA sequencing. According to Professor Liu, "Because tendons rarely heal well even with surgery, we were curious to know if p16INK4a+ cells could help in the repair of injured tendons as had been demonstrated in skin and lungs."
The study found that about seven days after tendon injury, there was a marked increase in p16INK4a+ cells within damaged tissue compared to healthy tendons where these cells were rare. Removing these cells resulted in poorer healing outcomes: weaker and less mature tendons with disorganized collagen fibers and increased inflammation around the injury site. Further analysis revealed that p16INK4a+ cells are mesenchymal connective tissue cells producing high levels of collagen as well as factors promoting new blood vessel and nerve formation.
Researchers also explored how these typically aging-associated cells switch into a repair mode following injury. They focused on epigenetic mechanisms involving JMJD3 protein, which removes an inhibitory gene mark called H3K27me3 from repair genes. Injured tendon tissues showed high JMJD3 levels and low H3K27me3 levels among p16INK4a+ mesenchymal cells, indicating activation of repair genes when needed for healing.
Additional experiments blocking or enhancing this pathway further confirmed its importance: inhibiting JMJD3 impaired healing while blocking EZH2 (which adds H3K27me3) improved collagen organization and mechanical strength during recovery.
The findings suggest that epigenetic modification enables certain senescent-like cells to transition into a reparative state during tendon healing. Targeting such pathways may offer new strategies for improving outcomes after tendon injuries.
