Tunable biomechanical niches regulate hepatic differentiation of mesenchymal stem cells for acute liver failure therapy

Acute liver failure (ALF) is a critical disease characterized by hepatocyte necrosis and liver dysfunction. Currently, effective treatments such as liver and hepatocyte transplantation are hindered by donor shortages. Consequently, hepatocyte-like cells (HLCs) derived from human adipose-derived mesenchymal stem cells (hADSCs) present substantial therapeutic potential as alternative cells. Establishing a supportive niche is conducive to regulating the differentiation of hADSCs into HLCs with the necessary metabolic and therapeutic functions. In this study, we develop a hydrogel-based synthetic niche composed of decellularized extracellular matrix (dECM) and oxidized dextran (ODex). These hydrogels, with tunable viscoelasticity and stiffness, regulate hepatic differentiation through Yes-associated protein (YAP) mechanotransduction. Specifically, a combination of faster stress relaxation rate and lower stiffness approximating that of mouse liver fosters the hepatic differentiation of hADSCs. Additionally, this niche also promotes HLC paracrine functions in pro-angiogenesis, anti-oxidative stress, and anti-inflammation. In vivo experiments reveal that hydrogel-based biomechanical niches-regulated HLCs demonstrate satisfactory therapeutic effects in mice with CCl₄-induced ALF. Overall, this hydrogel-based stem cell niche, which mimics the characteristics of the native liver, with optimized differentiation efficiency and therapeutic potential, offers a promising approach for leveraging biomaterials in liver tissue engineering.