Adenoviral Delivery of the VEGF and BMP-6 Genes to Rat Mesenchymal Stem Cells Potentiates Osteogenesis

Seamon, Jesse; Wang, Xiuli; Cui, Fuai; Keller, T C Steven; Dighe, Abhijit S.; Balian, Gary; Cui, Quanjun

doi:10.1155/2013/737580

Cited by 18 publications

(11 citation statements)

References 37 publications

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“…The transfected cells dramatically increased new bone formation and angiogenesis 5 weeks after surgery when compared to the nontransfected MSCs. Seamon et al [2013] subcutaneously injected MSCs transduced with adenoviral vector (Ad-VEGF + BMP-6) in rats. Analysis showed that only gene-transduced MSCs could induce osteogenesis in vivo, whereas adenoviral vector or nontransduced MSCs alone did not induce osteogenesis.…”

Section: Future Directions Of Msc Therapy In Clinical Practicementioning

confidence: 99%

Role of Mesenchymal Stem Cells in Bone Regenerative Medicine: What Is the Evidence?

Oryan

Kamali²,

Moshiri³

et al. 2017

Cells Tissues Organs

292

204

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Healing and regeneration of bone injuries, particularly those that are associated with large bone defects, are a complicated process. There is growing interest in the application of osteoinductive and osteogenic growth factors and mesenchymal stem cells (MSCs) in order to significantly improve bone repair and regeneration. MSCs are multipotent stromal stem cells that can be harvested from many different sources and differentiated into a variety of cell types, such as preosteogenic chondroblasts and osteoblasts. The effectiveness of MSC therapy is dependent on several factors, including the differentiating state of the MSCs at the time of application, the method of their delivery, the concentration of MSCs per injection, the vehicle used, and the nature and extent of injury, for example. Tissue engineering and regenerative medicine, together with genetic engineering and gene therapy, are advanced options that may have the potential to improve the outcome of cell therapy. Although several in vitro and in vivo investigations have suggested the potential roles of MSCs in bone repair and regeneration, the mechanism of MSC therapy in bone repair has not been fully elucidated, the efficacy of MSC therapy has not been strongly proven in clinical trials, and several controversies exist, making it difficult to draw conclusions from the results. In this review, we update the recent advances in the mechanisms of MSC action and the delivery approaches in bone regenerative medicine. We will also review the most recent clinical trials to find out how MSCs may be beneficial for treating bone defects.

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Section: Future Directions Of Msc Therapy In Clinical Practicementioning

confidence: 99%

Role of Mesenchymal Stem Cells in Bone Regenerative Medicine: What Is the Evidence?

Oryan

Kamali²,

Moshiri³

et al. 2017

Cells Tissues Organs

292

204

View full text Add to dashboard Cite

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“…Earlier we demonstrated that cloned MSCs transiently expressing VEGF and BMP‐6 genes, or VEGF and LMP‐1 genes, induce significantly greater osteogenesis in vivo than that induced by MSCs alone or MSCs expressing only one gene (Cui et al, ; Wang et al, ). We have also shown that primary MSCs fail to induce ectopic bone formation but adenoviral transfer of the VEGF and BMP‐6 genes enables these MSCs to induce bone formation successfully (Seamon et al, ). Moreover, we demonstrated that the addition of VEGF and BMP‐6 proteins to culture medium enhanced osteogenic differentiation of mouse bone marrow‐derived MSCs (Madhu et al, ) and hADSCs in vitro (Zhang et al, ).…”

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confidence: 99%

Cross‐Talk Between VEGF and BMP‐6 Pathways Accelerates Osteogenic Differentiation of Human Adipose‐Derived Stem Cells

Madhu

Balian

et al. 2015

Journal Cellular Physiology

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Deficiency in vascular endothelial growth factor (VEGF) or bone morphogenetic proteins (BMPs) results in fracture non-unions. Therefore, it is indispensable to comprehend the combined effect of VEGF and BMPs on the osteogenic differentiation of osteoprogenitor mesenchymal stem cells (MSCs) that are either naturally occurring at the fracture repair site or exogenously added to enhance the bone repair. We found that the combination of VEGF and BMP-6 enhanced COL1A2 expression, which correlated with upregulated expression of osterix, Dlx5, and Msx2 in human adipose-derived stem cells (hADSCs). Cross-talk between VEGF and BMP-6 pathways upregulated activation of p38 mitogen-activated kinase (p38 MAPK) and inhibited activation of protein kinase B (PKB, also known as Akt), whereas phosphorylation of "mothers against decapentaplegic" homologs 1/5/8 (Smads 1/5/8) and extracellular signal-regulated kinases 1 and 2 (ERK 1/2) was not affected. Consistent with these findings, p38 inhibitor SB203580, or siRNA knockdown of osterix, abrogated crosstalk between the VEGF and BMP-6 pathways and significantly reduced the observed upregulation of COL1A2. Nuclear translocation of the phosphorylated form of osterix was also inhibited by SB203580. Although crosstalk between the VEGF-BMP-6 pathways did not show an effect on the extent of mineralization, inhibition of any one of the three components that were upregulated through the cross-talk, i.e., osterix, Dlx5, and p38 activation, led to a complete inhibition of mineralization. Inhibition of PKB/Akt activation, which is attenuated through the cross-talk, significantly enhanced ALP gene expression. These observations imply that crosstalk between the VEGF and BMP-6 signaling pathways enhances osteogenic differentiation of MSCs.

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“…Genetic engineering approaches have been extensively explored to endow MSCs with enhanced regenerative capabilities to repair bone defects. A number of studies have demonstrated that the genetic modification of MSCs by the forced expression of various pro‐regenerative factors, such as BMP‐2, TGF‐β1, VEGF, and bFGF, improved bone formation and the repair of bone defects (Carpenter et al, 2010; Peng & Wang, 2017; Seamon et al, 2013). With the identification of an increasing number of miRNAs involved in osteogenesis, miRNA manipulation has become an important strategy for bone repair.…”

Section: Discussionmentioning

confidence: 99%

“…in mediating the enhanced osteogenic differentiation of hASCs by miR-146a suppression. improved bone formation and the repair of bone defects (Carpenter et al, 2010;Peng & Wang, 2017;Seamon et al, 2013). With the identification of an increasing number of miRNAs involved in osteogenesis, miRNA manipulation has become an important strategy for bone repair.…”

Section: Effects Of Immunomodulatory Products From Mir-146as-transdmentioning

confidence: 99%

Promotion of the immunomodulatory properties and osteogenic differentiation of adipose‐derived mesenchymal stem cells in vitro by lentivirus‐mediated mir‐146a sponge expression

Wan

et al. 2020

J Tissue Eng Regen Med

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Mesenchymal stem cells (MSCs) exert beneficial effects on the repair of bone tissue via both immunomodulatory functions and osteogenic differentiation. As one of the first miRNAs identified that regulate innate immune responses, miR-146a has been reported to serve as a negative-feedback regulator in several chronic inflammatory diseases. However, the majority of studies focus on understanding how miRNA-146a regulates immune cells and the associated immune-based disorders. In the present study, we employed miRNA sponges that were forcibly expressed using a lentiviral vector to knock down the expression of miR-146a in human adipose-derived stem cells (hASCs). The hASCs transduced with miR-146a sponges exhibited enhanced immunomodulatory properties, as evidenced by the increased production of key immunosuppressive factors. These factors were able to elevated expression of antiinflammatory genes and inhibited the expression of inflammatory genes in macrophages. Further mechanistic studies showed that the suppression of miR-146a activated NF-κB signaling in hASCs, suggesting its regulatory role in miR-146a spongeinduced immunomodulatory changes in hASCs. In addition, the suppression of miR-146a was also found to stimulate the osteogenic differentiation of hASCs. The observed upregulation of SMAD4 expression indicated the involvement of SMAD4 in modulating the osteogenic potential of hASCs in response to miR-146a suppression. Our study contributes to the understanding of the effects of miR-146a on the immunomodulatory properties and osteogenic differentiation of hASCs and highlights the potential use of miRNA-146a sponges modified hASCs as seed cells for bone tissue engineering.

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Adenoviral Delivery of the VEGF and BMP-6 Genes to Rat Mesenchymal Stem Cells Potentiates Osteogenesis

Cited by 18 publications

References 37 publications

Role of Mesenchymal Stem Cells in Bone Regenerative Medicine: What Is the Evidence?

Role of Mesenchymal Stem Cells in Bone Regenerative Medicine: What Is the Evidence?

Cross‐Talk Between VEGF and BMP‐6 Pathways Accelerates Osteogenic Differentiation of Human Adipose‐Derived Stem Cells

Promotion of the immunomodulatory properties and osteogenic differentiation of adipose‐derived mesenchymal stem cells in vitro by lentivirus‐mediated mir‐146a sponge expression

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