Sox11‐modified mesenchymal stem cells (MSCs) accelerate bone fracture healing: Sox11 regulates differentiation and migration of MSCs

Abstract

Mesenchymal stem cells (MSCs) are a promising cell resource for tissue engineering. Sry-related high-mobility group box 11 (Sox11) plays critical roles in neural development and organogenesis. In the present study, we investigated the role of Sox11 in regulating trilineage differentiation (osteogenesis, adipogenesis, and chondrogenesis) and migration of MSCs, and explored the effect of systemically administrated Sox11-modified MSCs on bone fracture healing using the rat model of open femur fracture. Our results demonstrated that Sox11 overexpression increased the trilineage differentiation and migration of MSCs, as well as cell viability under oxidative stress. The effect of Sox11 on osteogenesis was confirmed by ectopic bone formation assay conducted in nude mice. In addition, we found that Sox11 could activate the bone morphogenetic protein (BMP)/Smad signaling pathway in MSCs. By dual-luciferase reporter assay, we also demonstrated that Sox11 could transcriptionally activate runtrelated transcription factor 2 (Runx2) and CXC chemokine receptor-4 (CXCR4) expression. The activation of the BMP/Smad signaling pathway and Runx2, CXCR4 expression may have a synergic effect, which largely contributed to the effect of Sox11 on MSC fate determination and migration. Finally, using an open femur fracture model in rats, we found that a larger number of MSCs stably expressing Sox11 migrated to the fracture site and improved bone fracture healing. Taken together, our study shows that Sox11 is an important regulator of MSC differentiation and migration, and Sox11-modified MSCs may have clinical implication for accelerating bone fracture healing, which can reduce the delayed unions or non-

Mesenchymal Stem Cell Migration during Bone Formation and Bone Diseases Therapy

“…A similar result was obtained by Chen et al when they investigated the joint effects of MSCs with SDF-1α on bone formation in nonunion rat model [55]. It was also reported that Sox11 overexpression enhanced rat primary BMSC migration in vitro and in vivo and improved bone fracture healing when the MSCs with Sox11 overexpression were injected into a rat model with open femur fracture through the tail vein [56] (Table 2). …”

IGFBP7 regulates the osteogenic differentiation of bone marrow‐derived mesenchymal stem cellsviaWnt/β‐catenin signaling pathway

“…Fractures were generated in 8‐wk‐old male Sprague‐Dawley rats weighing ~250‐300 g. Rats were anesthetized with 0.3% pentobarbital sodium (Sigma‐Aldrich) intraperitoneally at 30 mg/kg body weight. The fracture model was established as previously described (38, 59, 60). An intramedullary needle (1.2‐mm diameter stainless steel syringe needle) was inserted inside the medullary canal of the tibia for fixation.…”

“…To evaluate the function of the experimental tibia, a 3‐point bending test was performed (59, 62). Both the experimental tibias and the contralateral intact tibias were tested.…”

Organ-specific migration of mesenchymal stromal cells: Who, when, where and why?

“…In a recent study by Xu and colleagues, Sryrelated high-mobility group box 11 (Sox11) overexpressing MSC were found to increase trilineage differentiation, migration, ectopic bone formation and that systemic administration could accelerate bone fracture healing in rats. Sox11 was found to induce BMP/Smad signaling and Runx2 and CXCR4 expression [68]. These studies demonstrate that recruitment of MSC to bone can be enhanced in order to therapeutically employ their osteogenic potential.…”