Hyaluronic Acid Hydrogel with Adjustable Stiffness for Mesenchymal Stem Cell 3D Culture via Related Molecular Mechanisms to Maintain Stemness and Induce Cartilage Differentiation

The stemness and differentiation characteristics of bone marrow mesenchymal stem cells (BMSCs) in three-dimensional (3D) culture are of great significance for stem cell therapy and cartilage tissue engineering repair. Moreover, due to their mechanical sensitivity, scaffold materials play important roles in various cell behaviors in 3D culture. In this study, the mechanical strength of hydrogel scaffolds was adjusted by changing the molecular weight of hyaluronic acid (HA). It was proven that BMSCs in a low-strength hydrogel could maintain stemness properties by activating the Wnt/β-catenin pathway for 1 week, while the high-molecular-weight hydrogel with a higher mechanical strength had the potential to promote the direction of cartilage differentiation of BMSCs by opening transient receptor potential vanilloid 4 (TRPV4)/Ca2+ molecular channels, also increasing the expression of type II collagen and SOX9 in BMSCs. This research has a certain reference value for the design of biomaterials for BMSCs' delivery in vivo, as well as the formulation of cartilage repair drug delivery programs based on molecular mechanisms.