Materials Stiffness-Dependent Redox Metabolic Reprogramming of Mesenchymal Stem Cells for Secretome-Based Therapeutic Angiogenesis

Cellular redox metabolism has emerged as a key tenet in stem cell biology that can profoundly influence the paracrine activity and therapeutic efficacy of mesenchymal stem cells (MSCs). Although the use of materials cues to direct the differentiation of MSCs has been widely investigated, little is known regarding the role of materials in the control of redox paracrine signaling in MSCs. Herein, using a series of mechanically tunable fibronectin-conjugated polyacrylamide (FN-PAAm) hydrogel substrates, it is shown that a mechanically compliant microenvironment with native-tissue mimicking stiffness (E = 0.15 kPa) can mechano-regulate the intracellular reactive oxygen species (ROS) level in human adipose-derived MSCs (ADMSCs). The cells reciprocate to the ROS imbalance by co-activating the nuclear factor erythroid 2–related factor 2 and hypoxia-inducible factor 1 alpha stress response signaling pathways to increase the production of vascular endothelial growth factor and basic fibroblast growth factor. Conditioned medium collected from ADMSCs grown on the 0.15 kPa FN-PAAm is found to significantly promote in vitro and ex ovo vascularization events. Collectively, these findings highlight the importance of delineating critical materials properties that can enable the reprogramming of cellular redox signaling for advanced MSCs-based secretome regenerative medicine.