Modulation of RhoA/ROCK-YAP/TAZ Axis enhances in situ adipogenesis in decellularized adipose-derived matrix hydrogels

Large-area soft tissue reconstruction represents a plastic surgery challenge. Decellularized adipose matrix (DAM) has emerged as a promising scaffold material for adipose tissue regeneration owing to its impressive adipogenic property. However, only a portion of DAM scaffolds can remodel into adipose tissue after implantation, while the remaining portion is replaced by fibrotic tissue. Mechanical stimulation is an important regulator of cell differentiation, and the signaling pathway RhoA/ROCK-YAP/TAZ axis plays a pivotal role during the process. In this study, the specific ROCK inhibitor Y-27632 was used to modulate RhoA/ROCK-YAP/TAZ axis in DAM hydrogel. The prepared hydrogels were successfully decellularized and exhibited a temperature-dependent sol-gel phase transition behavior. In vitro co-culture of ADSCs with Y-27632 loaded DAM hydrogels showed that the hydrogels possess good cytocompatibility, and can promote the adipogenic differentiation and reverse the phenotypic differentiation of ADSCs to myofibroblasts by inhibiting the RhoA/ROCK-YAP/TAZ axis. In a subcutaneous injection model of mice, Y-27632 loaded DAM hydrogels induced significant in situ adipogenesis. Overall, the adipogenic efficiency of DAM scaffolds was enhanced by loading DAM hydrogels with Y-27632, highlighting their promising potential for soft tissue reconstruction. The integration of DAM and mechanical signaling pathways brings new opportunities for in situ tissue regeneration with acellular soft tissue, and provides a cell free platform capable of restoring large-volume soft tissue defects by cell fate regulation.