Ligament injury in adult zebrafish triggers ECM remodeling and cell dedifferentiation for scar-free regeneration

After traumatic injury, healing of mammalian ligaments is typically associated with fibrotic scarring as opposed to scar-free regeneration. In contrast, here we show that the ligament supporting the jaw joint of adult zebrafish is capable of rapid and complete scar-free healing. Following surgical transection of the jaw joint ligament, we observe breakdown of ligament tissue adjacent to the cut sites, expansion of mesenchymal tissue within the wound site, and then remodeling of extracellular matrix (ECM) to a normal ligament morphology. Lineage tracing of mature ligamentocytes following transection shows that they dedifferentiate, undergo cell cycle re-entry, and contribute to the regenerated ligament. Single-cell RNA sequencing of the regenerating ligament reveals dynamic expression of ECM genes in neural-crest-derived mesenchymal cells, as well as diverse immune cells expressing the endopeptidase-encoding gene legumain. Analysis of legumain mutant zebrafish shows a requirement for early ECM remodeling and efficient ligament regeneration. Our study establishes a new model of adult scar-free ligament regeneration and highlights roles of immune-mesenchyme cross-talk in ECM remodeling that initiates regeneration.

Automated summary

This study reveals that the ligament supporting the jaw joint of adult zebrafish is capable of rapid and complete scar-free healing. The research shows that after surgical transection of the ligament, breakdown of ligament tissue, expansion of mesenchymal tissue, and remodeling of extracellular matrix occur, leading to the regeneration of a normal ligament. The study also highlights the importance of immune-mesenchyme cross-talk in ECM remodeling during the initiation of regeneration.