摘要：This work identified the important role of matrix mechanical plasticity in mediating fibroblast activation.Many existing studies have highlighted the important effects of biochemical cues(e.g.,transforming growth factor-β1)and mechanicalstiffness on fibroblast activation.Our results indicated that self-assembled collagen hydrogels showed high plasticity and in which fibroblasts remain undifferentiated.However,when we decreased the plasticity of collagen hydrogels by increasing covalent crosslinking,fibroblasts showed a significant fibrotic response as reflected by the increasedα-SMA expression.Since the material systems we constructed have low and the same initial modulus,this process is stiffness independent.Although it has been reported that covalently crosslinked hydrogels are more difficult to degrade and matrix degradability has an important impact on cell behaviors,no significant changes of fibroblast activation were observed when proteases were broadly inhibited in our experiments.Importantly,the hydrogels we constructed showed similar plastic behaviors under creep and recovery tests compared to native normal and fibrotic tissues.These highlight the importance of matrix plasticity in mimicking the mechanical microenvironment of native fibrotic tissues.Mechanistically,we found that the enhanced fibroblast activation in low plastic matrix is mediated through integrin-actin pathway and nuclear localization of YAP.In high plastic collagen,matrix cannot provide effective resistance to actin contraction because of the rupture of weak crosslinks and the slippage of local fibers.On the contrary,in low plastic collagen,deformation energy can be stored in the network due to the existence of strong covalent crosslinks,thus enabling the build-up of cell traction and the formation of a robust cell-matrix interaction.Experiments of inhibiting or promoting cytoskeletal contractility and CGMD simulation both verified the above points.Our results clarify plasticity changes on the development of fibrotic diseases and high

注：因版权方要求，不能公开全文，如需全文，请咨询杂志社