On-Demand Local Immunomodulation via Epigenetic Control of Macrophages Using an Inflammation-Responsive Hydrogel for Accelerated Wound Healing.

Effective resolution of inflammation contributes to favorable tissue regenerative therapeutic outcomes. However, fine coordination of local immunomodulation in a timely manner is limited because of the lack of strategies for controlling disease dynamics. We developed an inflammation-responsive hydrogel (IFRep gel) as an effective therapeutic strategy for on-demand epigenetic modulation against disease dynamics in wound healing. The IFRep gel is designed to control drug release by cathepsins according to the state of inflammation for active disease treatment. The gel loaded with an inhibitor of the epigenetic reader bromodomain (BRD)4 regulates the translocation of nuclear factor erythroid 2 to the nucleus, where it promotes antioxidant gene expression to reverse the inflammatory macrophage state in vitro. In addition, on-demand BRD inhibition using the responsive hydrogel accelerates wound healing by controlling the early inflammatory phase and keratinocyte activation in vivo. Our data demonstrate the clinical utility of using the IFRep gel as a promising strategy for improving therapeutic outcomes in inflammation-associated diseases.

FGF2-primed 3D spheroids producing IL-8 promote therapeutic angiogenesis in murine hindlimb ischemia.

Peripheral artery disease is a progressive, devastating disease that leads to critical limb ischemia (CLI). Therapeutic angiogenesis using stem cell therapy has emerged as a promising approach for its treatment; however, adapting cell-based therapy has been limited by poor cell survival and low treatment efficiency. To overcome unmet clinical needs, we developed a fibroblast growth factor 2 (FGF2)-immobilized matrix that enabled control of cell adhesion to the surface and exerted a priming effect on the cell. Human adipose-derived stem cells (hASCs) grown in this matrix formed a functionally enhanced cells spheroid (FECS-Ad) that secreted various angiogenic factors including interleukin-8 (IL-8). We demonstrated that IL-8 was upregulated by the FGF2-mediated priming effect during FECS-Ad formation. Immobilized FGF2 substrate induced stronger IL-8 expression than soluble FGF2 ligands, presumably through the FGFR1/JNK/NF-κB signaling cascade. In IL-8-silenced FECS-Ad, vascular endothelial growth factor (VEGF) expression was decreased and angiogenic potential was reduced. Intramuscular injection of FECS-Ad promoted angiogenesis and muscle regeneration in mouse ischemic tissue, while IL-8 silencing in FECS-Ad inhibited these effects. Taken together, our data demonstrate that IL-8 contributes to therapeutic angiogenesis and suggest that FECS-Ad generated using the MBP-FGF2 matrix might provide a reliable platform for developing therapeutic agents to treat CLI.