Time-adaptable alterations of the extracellular matrix during chondrocyte dedifferentiation

Cartilage damage as a universal health problem, remains a significant cause for the development of osteoarthritis, affecting more than one million people worldwide. Poor intrinsic capacity for healing and available therapeutic strategies have severely restricted the cartilage repair post damage. Decellularized extracellular matrix (ECM) provides new thinking for the treatment of cartilage defect. However, chondrocytes dedifferentiation brings uncertainty to the researches and applications of chondrocyte-derived decellularized matrix. In this study, we demonstrated the nuclear deformation during chondrocyte dedifferentiation process, consummating the time-lapse theory atlas of chondrocyte dedifferentiation. We manufactured decellularized chondrocyte sheets (dCS) derived from different stages of dedifferentiated chondrocytes, and performed multimodal assays to characterize the mechanical, physiochemical, and proteomic properties of the dCS. Collagen II peaked at the dCS derived from plastic passage 2 chondrocytes, and decreased at the late dCS. Collagen I increased under temporal correlation. The randomness of collagen fiber direction decreased under temporal correlation, positively correlated with the ultimate tensile strength. Compared with the late dCS, the early dCS promoted cell migration, proliferation, and chondrogenic differentiation. The supplement of Fmod upregulated the biological regulatory activity of the late dCS on the chondrocyte dedifferentiation process. Overall, this study lays a foundation to improve the theory atlas of chondrocyte dedifferentiation, provides insights into cartilage repair and lay a basis for the development of new materials for cartilage repair.