Exercise Induced Endothelial Mesenchymal Transition (EndMT) Facilitates Meniscal Fibrocartilage Regeneration.

The meniscus is a semilunar wedge-shaped fibrocartilage tissue within the knee joint that is important for withstanding mechanical shock during joint motion. The intrinsic healing capacity of meniscus tissue is very limited, which makes meniscectomy the primary treatment method in the clinic. An effective translational strategy for regenerating the meniscus after total or subtotal meniscectomy, particularly for extensive meniscal lesions or degeneration, is yet to be developed. The present study demonstrates that the endothelial mesenchymal transition (EndMT) contributes to meniscal regeneration. The mechanical stimulus facilitated EndMT by activating TGF-β2 signaling. A handheld bioprinter system to intraoperatively fabricate a porous meniscus scaffold according to the resected meniscus tissue is developed; this can simplify the scaffold fabrication procedure and period. The transplantation of a porous meniscus scaffold combined with a postoperative regular exercise stimulus facilitated the regeneration of anisotropic meniscal fibrocartilaginous tissue and protected the joint cartilage from degeneration in an ovine subtotal meniscectomy model. Single-cell RNA sequencing and immunofluorescence co-staining analyses further confirmed the occurrence of EndMT during meniscal regeneration. EndMT-transformed cells gave rise to fibrochondrocytes, subsequently contributing to meniscal fibrocartilage regeneration. Thus, an efficient translational strategy to facilitate meniscal regeneration is developed.