Genetically engineered MSCs overexpressing hepatocyte growth factor for the treatment of human refractory wounds

Refractory wounds (RWs) are a common and severe complication of many diseases; however, the existing therapeutic methods are unsatisfactory in clinical practice. Here, we observed significant downregulation of the hepatocyte growth factor (HGF) in plasma samples from patients with autoimmune diseases. We used electroporation to deliver a plasmid containing HGF to induce its overexpression on mesenchymal stromal cells (MSC^HGF) and loaded them into an injectable hydrogel to treat RWs in patients with clinical autoimmunity. The MSC^HGF exhibited stable HGF expression and secretion. In addition, they displayed a self-reinforcing loop, enhanced migration, and improved anti-apoptosis capacity via the autocrine activation of the c-Met-mediated phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway. Furthermore, the HGF (as well as other bioactive factors) secreted from the MSC^HGF significantly augmented the migration and angiopoiesis of vascular endothelial cells, decreased the cellular inflammation of macrophages, and improved extracellular matrix remodeling in fibroblasts. According to these features, we demonstrated that the MSC^HGF-loaded injectable hydrogel boosted cellular functions and afforded a long-acting healing efficacy in the treatment of clinical autoimmune patients with RWs. Therefore, the genetically engineered MSC^HGF and their dispersed hydrogel system will have clinical significance for wound therapy.