Bioinspired Collagen Scaffold Loaded with bFGF-Overexpressing Human Mesenchymal Stromal Cells Accelerating Diabetic Skin Wound Healing via HIF-1 Signal Pathway Regulated Neovascularization

The healing of severe chronic skin wounds in chronic diabetic patients is still a huge clinical challenge due to complex regeneration processes and control signals. Therefore, a single approach is difficult in obtaining satisfactory therapeutic efficacy for severe diabetic skin wounds. In this study, we adopted a composite strategy for diabetic skin wound healing. First, we fabricated a collagen-based biomimetic skin scaffold. The human basic fibroblast growth factor (bFGF) gene was electrically transduced into human umbilical cord mesenchymal stromal cells (UC-MSCs), and the stable bFGF-overexpressing UC-MSCs (bFGF-MSCs) clones were screened out. Then, an inspired collagen scaffold loaded with bFGF-MSCs was applied to treat full-thickness skin incision wounds in a streptozotocin-induced diabetic rat model. The mechanism of skin damage repair in diabetes mellitus was investigated using RNA-Seq and Western blot assays. The bioinspired collagen scaffold demonstrated good biocompatibility for skin-regeneration-associated cells such as human fibroblast (HFs) and endothelial cells (ECs). The bioinspired collagen scaffold loaded with bFGF-MSCs accelerated the diabetic full-thickness incision wound healing including cell proliferation enhancement, collagen deposition, and re-epithelialization, compared with other treatments. We also showed that the inspired skin scaffold could enhance the <i>in vitro</i> tube formation of ECs and the early angiogenesis process of the wound tissue <i>in vivo</i>. Further findings revealed enhanced angiogenic potential in ECs stimulated by bFGF-MSCs, evidenced by increased AKT phosphorylation and elevated HIF-1α and HIF-1β levels, indicating the activation of HIF-1 pathways in diabetic wound healing. Based on the superior biocompatibility and bioactivity, the novel bioinspired skin healing materials composed of the collagen scaffold and bFGF-MSCs will be promising for healing diabetic skin wounds and even other refractory tissue regenerations. The bioinspired collagen scaffold loaded with bFGF-MSCs could accelerate diabetic wound healing via neovascularization by activating HIF-1 pathways.