Therapeutic potential of gelatine methacrylate hydrogels loaded with macrophage-derived exosomes for accelerating angiogenesis and cutaneous wound healing

Abstract

Extensive studies demonstrate that macrophage response plays an important role in regulating angiogenesis via a paracrine way, which is crucial for skin wound repair. This study isolated and characterized nanosized exosomes from differently polarized macrophages (MΦ), including M0 (naïve), M1 (pro-inflammatory), and M2 (anti-inflammatory) macrophages, and further assessed their impacts on angiogenesis and skin regeneration. Our results indicated that compared to M0 and M1 counterparts, M2 macrophage-derived exosomes (M2-Exos) exhibited a pronounced ability to promote angiogenic ability of of human umbilical vein endothelial cells (HUVECs) by enhancing expression of angiogenic genes and proteins, increasing cell migration, and improving tubulogenesis. Bioinformatics analyses suggested that the distinct angiogenic potentials of three MΦ-Exos might be attributed to the differentially expressed angiogenesis-related miRNAs and their target genes such as Stat3, Smad 2, and Smad4. Moreover, these isolated MΦ-Exos were integrated with gelatine methacrylate (GelMA) hydrogels to achieve the sustained delivery at murine full-thickness cutaneous wound sites. In vivo results showed that Gel/M2-Exos significantly augmented angiogenesis, accelerated re-epithelialization, promoted collagen maturity, thereby promoting wound healing. In contrary, Gel/M1-Exos showed the opposite effects. Our findings provided compelling evidence that the polarization status of macrophages significantly affected angiogenesis and wound healing via the miRNA cargos of their derived exosomes. Moreover, this study opens a new avenue for developing nano-scale, cell-free exosome-based therapies in treating cutaneous wounds. Graphical abstract

Integrating Bioactive Graded Hydrogel with Radially Aligned Nanofibers to Dynamically Manipulate Wound Healing Process

“…Vascular regeneration plays a crucial role in promoting oxygen and essential nutrient transport, while also eliminating metabolic products. − Immunohistochemical staining of CD31 and α-SMA was employed to assess vascular regeneration during wound healing. CD31, a transmembrane protein, is expressed during early angiogenesis and serves as an alternative marker for evaluating endothelial cell differentiation and its impact on angiogenesis during wound recovery .…”