Artificial human stem cell niche created in cartilage-inspired hydrogel for enhanced articular cartilage regeneration

Stem cell-based therapies and liposome-integrated hydrogel matrix strategies are promising for articular cartilage regeneration. However, challenges persist due to the loss of stemness during in vitro expansion and the lack of control over stem cell behavior in vivo. Herein, we design a cartilage-inspired hydrogel scaffold similar to the native stem cell niche and expect to enhance chondrogenesis for cartilage repair. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are encapsulated within a composite hydrogel composed of methacrylate hyaluronic acid and collagen networks, mimicking the extracellular matrix of native cartilage. Additionally, embedded liposomes participate to form a lubrication mechanism, the boundary layer in the synovial joints, which lowers the coefficient of friction close to the native level. In vitro, our hydrogel niche system enhances cell-cell and cell-matrix interactions, induces hUC-MSCs mesenchymal condensation, establishes the hypoxic microenvironment formation, and therefore improves the chondrogenic differentiation. Moreover, SOX9, COL2, and HIF-1α expression are all upregulated, whereas MMP13 is downregulated. Meanwhile, in vivo implantation in an osteochondral defect model demonstrates our repair strategy is superior to the conventional hydrogel scaffolds. The advantages include the restoration of PRG4, the suppression of MMP13 and the increasement of ICRS II score to the native levels at 6 weeks post-implantation. These findings are important biophysical cues in regulating stem cell fate in a three-dimensional hydrogel niche and conducive to developing biomimetic scaffolds for cartilage repair.