Ligament injury in adult zebrafish triggers ECM remodeling and cell dedifferentiation for scar-free regeneration.
Publication Year:
2023
PubMed ID:
37726321
Funding Grants:
Public Summary:
In mammals, when ligaments are injured, they often heal with the formation of scar tissue. However, a study in adult zebrafish has revealed a remarkable ability for scar-free healing in the jaw joint ligament. After surgically cutting this ligament, the researchers observed a breakdown of tissue near the injury, followed by the expansion of mesenchymal tissue in the wound site. This tissue then transformed into a normal ligament structure. The study also found that mature ligament cells underwent dedifferentiation, re-entered the cell cycle, and contributed to the regenerated ligament. Single-cell analysis of the regenerating ligament showed that neural-crest-derived mesenchymal cells expressed genes related to the extracellular matrix (ECM), and various immune cells expressed a gene called legumain, which is involved in tissue remodeling. Mutant zebrafish lacking legumain exhibited difficulties in ECM remodeling and efficient ligament regeneration. This research introduces a novel model for scar-free ligament regeneration in adults and highlights the role of communication between immune cells and mesenchymal cells in initiating the tissue's regeneration.
Scientific Abstract:
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.