biostudies-literatureUnknown16(1)Blumenkrantz MAdult mammalian synovial joints have limited regenerative capacity, where injuries heal with mechanically inferior fibrotic tissues. Here we developed a unilateral whole-joint resection model in adult zebrafish to advance our understanding of how to stimulate regrowth of native synovial joint tissues. Using a combination of microCT, histological, live imaging, and single-cell RNA sequencing (scRNAseq) approaches after complete removal of all joint tissues, we find de novo regeneration of articular cartilage, ligament, and synovium into a functional joint. Clonal lineage tracing and scRNAseq implicate a multipotent, neural crest-derived population in the adult skeleton as a cell source for these regenerating tissues. Together, our findings reveal latent molecular and cellular programs within the adult skeleton that are deployed to regenerate a complex joint with lubricated articular cartilage.Nature communications8570https://www.ebi.ac.uk/biostudies/studies/S-EPMC12480486biostudies-literatureDynamic cell fate plasticity and tissue reintegration drive functional adult synovial joint regeneration after complete resection.PMC12480486Gagarin EGwin MChahine NOBlumenkrantz MKamel MHMo JSherwood DAnderson TGeras ADumitrascu BSmeeton JCampos LWoron FWeinstein EfalseDynamic cell fate plasticity and tissue reintegration drive functional adult synovial joint regeneration after complete resection.Adult mammalian synovial joints have limited regenerative capacity, where injuries heal with mechanically inferior fibrotic tissues. Here we developed a unilateral whole-joint resection model in adult zebrafish to advance our understanding of how to stimulate regrowth of native synovial joint tissues. Using a combination of microCT, histological, live imaging, and single-cell RNA sequencing (scRNAseq) approaches after complete removal of all joint tissues, we find de novo regeneration of articular cartilage, ligament, and synovium into a functional joint. Clonal lineage tracing and scRNAseq implicate a multipotent, neural crest-derived population in the adult skeleton as a cell source for these regenerating tissues. Together, our findings reveal latent molecular and cellular programs within the adult skeleton that are deployed to regenerate a complex joint with lubricated articular cartilage.2025-01-01T00:00:00Z2025 Sep2026-06-04T05:09:19.112Z2026-05-05T03:12:45.549ZS-EPMC124804864102278510.1038/s41467-025-63596-8