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Aqp1 enhances migration of bone marrow mesenchymal stem cells through regulation of FAK and ?-catenin.

ABSTRACT: Bone marrow mesenchymal stem cells (MSCs) have the potential to migrate to the site of injury and regulate the repair process. Aquaporin 1 (Aqp1) is a water channel molecule and a regulator of endothelial cell migration. To study the role of Apq1 in MSC migration, we manipulated the expression of the Aqp1 gene in MSCs and explored its effects on MSC migration both in vitro and in vivo. Overexpression of Aqp1 promoted MSC migration, while depletion of Aqp1 impaired MSC migration in vitro. When the green fluorescent protein (GFP) labeled Aqp1 overexpressing MSCs were systemically injected into rats with a femoral fracture, there were significantly more GFP-MSCs found at the fracture gap in the Aqp1-GFP-MSC-treated group compared to the GFP-MSC group. To elucidate the underlying mechanism, we screened several migration-related regulators. The results showed that ?-catenin and focal adhesion kinase (FAK) were upregulated in the Aqp1-MSCs and downregulated in the Aqp1-depleted MSCs, while C-X-C chemokine receptor type 4 had no change. Furthermore, ?-catenin and FAK were co-immunoprecipitated with Aqp1, and depletion of FAK abolished the Aqp1 effects on MSC migration. This study demonstrates that Aqp1 enhances MSC migration ability mainly through the FAK pathway and partially through the ?-catenin pathway. Our finding suggests a novel function of Aqp1 in governing MSC migration, and this may aid MSC therapeutic applications.

SUBMITTER: Meng F

PROVIDER: S-EPMC3870604 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Aqp1 enhances migration of bone marrow mesenchymal stem cells through regulation of FAK and β-catenin.

Meng Fanbiao F Rui Yunfeng Y Xu Liangliang L Wan Chao C Jiang Xiaohua X Li Gang G

Stem cells and development 20130927 1

Bone marrow mesenchymal stem cells (MSCs) have the potential to migrate to the site of injury and regulate the repair process. Aquaporin 1 (Aqp1) is a water channel molecule and a regulator of endothelial cell migration. To study the role of Apq1 in MSC migration, we manipulated the expression of the Aqp1 gene in MSCs and explored its effects on MSC migration both in vitro and in vivo. Overexpression of Aqp1 promoted MSC migration, while depletion of Aqp1 impaired MSC migration in vitro. When th ...[more]

PMID: 23962074

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Project description:BackgroundManagement of fracture healing with a large bone defect remains a tricky subject in orthopedic trauma. Enhancing osteogenesis of human bone marrow-derived mesenchymal stem cells (hBMSCs) is one of the useful therapeutic strategies for fracture healing. Previous studies have revealed that Apelin may play an important role in bone metabolism. However, its function in the osteogenesis of hBMSCs remains unclear. Therefore, in this study, we investigated the effects and mechanism of Apelin on osteogenic differentiation.MethodsWe investigated the osteogenesis effects of hBMSCs by both exogenous Apelin protein and overexpression Apelin in vitro. Cell proliferation assay was used to assess the effect of Apelin on the proliferation of hBMSCs. ALP staining and Alizarin Red staining were used to evaluate ALP activity and mineral deposition respectively. qPCR and Western blotting analysis were used to detect the expression of target genes and proteins. In vivo, a rat tibial osteotomy model was established; radiographic analysis and histological evaluation were used to confirm the therapeutic effects of Apelin in fracture healing. Statistical significance was determined by two-tailed Student's t test when 2 groups were compared. When more than 2 groups were compared, one-way ANOVA followed by Bonferroni's post-hoc test was used. And two-way ANOVA, followed by Bonferroni multiple comparisons post-hoc test, was performed when the treatment groups at different time points were compared.ResultsThe addition of exogenous Apelin protein or overexpression of Apelin promoted osteoblast differentiation of hBMSCs in vitro. Increased mineral deposits were observed after treatment with extracellular Apelin protein or after the upregulation of Apelin. Moreover, ?-catenin levels were upregulated by Apelin. The enhancement of osteogenic differentiation induced by Apelin was attenuated by specific Wnt/?-catenin signaling pathway inhibitors. In a rat tibial osteotomy model, local injection of exogenous Apelin protein improved bone healing, as demonstrated by imaging and histological analyses.ConclusionsTaken together, these findings indicate that Apelin regulates osteogenic differentiation of hMSCs partly via the Wnt/?-catenin signaling pathway and effectively promotes fracture healing.

Project description:BackgroundGlobally, bone fractures are the most common musculoskeletal trauma, and approximately 8-10% of cases that fall into the categories of delayed or non-union healing. To date, there are no efficient pharmacological agents to accelerate the healing of bone fractures. Thus, it is necessary to find new strategies that accelerate bone healing and reduce the incidence of non-union or delayed fracture healing. Previous studies have revealed that the plasminogen activation system has been demonstrated to play an important role in bone metabolism. However, the function of SERPINB2 in the osteogenesis of hBMSCs remains unclear. Therefore, in this study, we investigated the effects and mechanism of SERPINB2 on osteogenic differentiation.MethodsWe investigated the osteogenesis effects of hBMSCs by both exogenous SerpinB2 protein and SERPINB2 gene silencing in vitro. Cell proliferation assay was used to assess the effect of exogenous SerpinB2 or SERPINB2 silencing on proliferation of hBMSCs. qPCR and Western blotting analysis detected the expression of target genes and proteins respectively. ALP staining was used to evaluated ALP activity and Alizarin Red staining (ARS) was used to evaluate mineral deposition. In vivo, a murie tibial fracture model was established, histological evaluation and radiographic analysis was used to confirm the therapeutic effects of SERPINB2 silencing in fracture healing. Statistical significance between two groups was determined by Student's t test, one-way ANOVA or Bonferroni's post-hoc test according to the distribution of the tested population.ResultsThe addition of exogenous SerpinB2 protein inhibted osteoblast differentiation of hBMSCs in vitro, while SERPINB2 gene silencing significant promote osteoblast differentiation of hBMSCs in vitro. And silenced SERPINB2 gene also increased mineral deposits. Moreover, β-catenin levels were up-regulated by SERPINB2 gene depletion. And the enhancement of osteogenic differentiation induced by SERPINB2 silencing was almost inhibited by specific Wnt/β-catenin signaling pathway inhibitor. In a murine tibial fracture model, local injection of SERPINB2 siRNA improved bone fracture healing.ConclusionsTaken together, these findings indicate that SERPINB2 silencing promoted osteogenic differentiation of BMSCs via the Wnt/β-catenin signaling pathway, and silenced SERPINB2 in vivo effectively promotes fracture healing, suggesting that SERPINB2 may be a novel target for bone fracture healing.

Dataset Information

Aqp1 enhances migration of bone marrow mesenchymal stem cells through regulation of FAK and ?-catenin.

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Aqp1 enhances migration of bone marrow mesenchymal stem cells through regulation of FAK and β-catenin.

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