Abstract
Fracture nonunion and delayed union continue to pose challenges for orthopedic surgeons. In the present study, we combined HMGB1 gelatin sponges with MSC sheets to promote bone healing after surgical treatment of rat tibial fractures. The HMGB1 gelatin sponge scaffolds supported the expansion of mesenchymal stem cells (MSCs) and promoted the osteogenic differentiation of MSCs and MSC sheets. Lentiviral vectors were then used to overexpress HMGB1 in MSCs. The results indicated that HMGB1 promotes the osteogenic differentiation of MSCs through the STAT3 pathway. Both siRNA and a STAT3 inhibitor downregulated STAT3, further confirming that HMGB1 induces the osteogenic differentiation of MSCs partly via the STAT3 signal pathway. In a rat tibial osteotomy model, we demonstrated the ability of HMGB1 gelatin sponge scaffolds to increase bone formation. The addition of MSC sheets further enhanced fracture healing. These findings support the use of HMGB1-loaded gelatin sponge scaffolds combined with MSC sheets to enhance fracture healing after surgical intervention.
Highlights
Fracture nonunion or delayed union continues to pose challenges for orthopedic surgeons
Our results showed that the addition of high mobility group box-1 protein (HMGB1) to the gelatin sponge scaffolds improved their biocompatibility in terms of supporting mesenchymal stem cells (MSC) proliferation in vitro, as well as the osteogenic differentiation of MSCs and MSC sheets
Extracellular HMGB1 acts as a chemoattractant directing MSC migration and enhancing the differentiation of osteogenic and angiogenic stem cells after tissue damage [21,22,23].Horst et al [24] showed that HMGB1 expression was markedly increased in the fracture hematoma that developed in a pig model of bone fracture
Summary
Fracture nonunion or delayed union continues to pose challenges for orthopedic surgeons. Tissue engineering has shown promise in bone regeneration. Growth factors play key roles in the “diamond concept” of fracture healing [4, 5]. Combinations of exogenous bone morphogenetic proteins (BMPs) and scaffolds in animal models of tissue engineering improve healing [6, 7]. BMPs have failed to exhibit the anticipated efficacies, both during fracture healing and when used to treat tibial non-union [8,9,10]. HMGB1 has been shown to promote osteogenesis. Hsu et al [11] reported that HMGB1 promoted the osteogenesis of adipose tissue-derived stem cells. The potential of HMGB1 as an osteogenic cytokine augmenting local bone regeneration merited further investigation
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