High-mobility group protein box 1 (HMGB1) gene delivery induces angiogenesis in rat myocardial infarction model

Objective: HMGB1 protein (High-mobility group box 1) is a DNA-binding protein that mediates inflammatory responses in various organ systems. Recent studies indicate that HMGB1 is a strong chemokine for stem cell recruitment and tissue regeneration after injury. However, the underlying mechanism is still unclear. In this study we aimed to evaluate the effects of extracellular HMGB1 on mesenchymal stem cell migration, proliferation and angiogenesis in vitro and in vivo in rat acute myocardial infarction model by gene therapy approach.

Methods: The cellular effect of HMGB1 was evaluated in mouse mesenchymal stem cell in vitro. The cytoskeleton reorganization of was examined by fluorescein-conjugated phalloidin. Boyden chamber and XTT (2.3-Bis [2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide) cell proliferation assay used to assess the migration and the proliferation of mesenchymal stem cells respectively. HMGB-1 gene complex was injected directly into the infarcted heart after intravenous injection of BrdU-labelled mesenchymal stem cells.

Results: The presence of HMGB1 enhanced mesenchymal stem cell migration although did not significantly contribute to their proliferation in vitro. Meanwhile HMGB1 also induce transient mesenchymal stem cell actin filament reorganization. Stress fibers were formed to a similar extent as with VEGF. 53±10% more BrdU+ cells were found to migrate to the border zone after 3 weeks. A significant improvement in capillary density has also been observed in the infarcted heart treated with the HMGB1 gene.

Conclusion: Thus HMGB1 could be a potent chemokine directing the migration of stem cells to injuried heart and promoting tissue regeneration.