Soft Material Approach to Induce Oxidative Stress in Mesenchymal Stem Cells for Functional Tissue Repair

Biomimicking hydrogel-based cell culture platforms with physiologically relevant stiffness are powerful tools to modulate the behaviors of stem cells. Herein, the use of fibronectin-conjugated polyacrylamide (PAA) hydrogel biointerface is exploited to modulate the intracellular oxidative stress of human bone marrow derived mesenchymal stem cells (MSCs). We show that compliant culture surface with kPa range matrix stiffness can augment the expression level of reactive oxygen species (ROS) in MSCs by approximately 2-4 fold compared with cells grown on conventional FN coated glass control surface in a noncytotoxic manner. Via an unbiased proteomics approach and mechanistic studies, we show that the secretion level of a sub series of "mechano-sensitive" chemokines and trophic factors is heavily dependent on the PAA matrix stiffness mediated ROS level. Importantly, the secretome harvested from the cells that were grown on the PAA hydrogel was found to enhance wound healing in both in vitro and in vivo full thickness mouse excisional wound model. The devised "soft approach" to induce oxidative stress in MSCs is posited to pave the way for novel cell-free therapeutic interventions targeting a wide variety of diseases and to foster functional tissue repair.