Delivery of dimethyloxalylglycine in calcined bone calcium scaffold to improve osteogenic differentiation and bone repair

AbstractAdipose-derived mesenchymal stem cells (ADSCs) are promising candidate for regenerative medicine to repair non-healing bone defects due to their high and easy availability. However, the limited osteogenic differentiation potential greatly hinders the clinical application of ADSCs in bone repair. Accumulating evidences demonstrate that circular RNAs (circRNAs) are involved in stem/progenitor cell fate determination, but their specific role in stem/progenitor cell osteogenesis, remains mostly undescribed. Here, we show that circRNA-vgll3 originating from the vgll3 locus markedly enhances osteogenic differentiation of ADSCs; nevertheless, silencing of circRNA-vgll3 dramatically attenuates ADSC osteogenesis. Furthermore, we validate that circRNA-vgll3 functions in ADSC osteogenesis through a circRNA-vgll3/miR-326-5p/integrin α5 (Itga5) pathway. Itga5 promotes ADSC osteogenic differentiation and miR-326-5p suppresses Itga5 translation. CircRNA-vgll3 directly sequesters miR-326-5p in the cytoplasm and inhibits its activity to promote osteogenic differentiation. Moreover, the therapeutic potential of circRNA-vgll3-modified ADSCs with calcium phosphate cement (CPC) scaffolds was systematically evaluated in a critical-sized defect model in rats. Our results demonstrate that circRNA-vgll3 markedly enhances new bone formation with upregulated bone mineral density, bone volume/tissue volume, trabeculae number, and increased new bone generation. This study reveals the important role of circRNA-vgll3 during new bone biogenesis. Thus, circRNA-vgll3 engineered ADSCs may be effective potential therapeutic targets for bone regenerative medicine.

Download Full-text

Exendin‑4 promotes osteogenic differentiation of adipose‑derived stem cells and facilitates bone repair

Molecular Medicine Reports ◽

10.3892/mmr.2019.10764 ◽

2019 ◽

Author(s):

Banglian Deng ◽

Wenzhong Zhu ◽

Yansheng Duan ◽

Yuqian Hu ◽

Xuefeng Chen ◽

...

Keyword(s):

Stem Cells ◽

Osteogenic Differentiation ◽

Bone Repair ◽

Adipose Derived Stem Cells

Download Full-text

Transcription factor 7-like 2 promotes osteogenic differentiation and boron-induced bone repair via lipocalin 2

Materials Science and Engineering C ◽

10.1016/j.msec.2020.110671 ◽

2020 ◽

Vol 110 ◽

pp. 110671

Author(s):

Chengcheng Yin ◽

Xiaoshi Jia ◽

Qin Zhao ◽

Zifan Zhao ◽

Jinyang Wang ◽

...

Keyword(s):

Transcription Factor ◽

Osteogenic Differentiation ◽

Bone Repair ◽

Lipocalin 2

Download Full-text

Human β-defensin 3 gene modification promotes the osteogenic differentiation of human periodontal ligament cells and bone repair in periodontitis

International Journal of Oral Science ◽

10.1038/s41368-020-0078-6 ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Lingjun Li ◽

Han Jiang ◽

Rixin Chen ◽

Jing Zhou ◽

Yin Xiao ◽

...

Keyword(s):

Osteogenic Differentiation ◽

Periodontal Ligament ◽

Bone Repair ◽

Periodontal Ligament Cells ◽

Gene Modification ◽

Human Periodontal Ligament Cells

Download Full-text

Adenovirus-mediated expression of vascular endothelial growth factor-a potentiates bone morphogenetic protein9-induced osteogenic differentiation and bone formation

Biological Chemistry ◽

10.1515/hsz-2015-0296 ◽

2016 ◽

Vol 397 (8) ◽

pp. 765-775 ◽

Cited By ~ 2

Author(s):

Chang-jun Pi ◽

Kai-lu Liang ◽

Zhen-yong Ke ◽

Fu Chen ◽

Yun Cheng ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Bone Formation ◽

Osteogenic Differentiation ◽

Bone Repair ◽

Osteoporotic Fractures ◽

Angiogenic Factor ◽

Vascular Endothelial ◽

Akt Inhibitor ◽

Endothelial Growth Factor

Abstract Mesenchymal stem cells (MSCs) are suitable seed cells for bone tissue engineering because they can self-renew and undergo differentiation into osteogenic, adipogenic, chondrogenic, or myogenic lineages. Vascular endothelial growth factor-a (VEGF-a), an angiogenic factor, is also involved in osteogenesis and bone repair. However, the effects of VEGF-a on osteogenic MSCs differentiation remain unknown. It was previously reported that bone morphogenetic protein9 (BMP9) is one of the most important osteogenic BMPs. Here, we investigated the effects of VEGF-a on BMP9-induced osteogenesis with mouse embryo fibroblasts (MEFs). We found that endogenous VEGF-a expression was undetectable in MSCs. Adenovirus-mediated expression of VEGF-a in MEFs potentiated BMP9-induced early and late osteogenic markers, including alkaline phosphatase (ALP), osteocalcin (OCN), and osteopontin (OPN). In stem cell implantation assays, VEGF-a augmented BMP9-induced ectopic bone formation. VEGF-a in combination with BMP9 effectively increased the bone volume and osteogenic activity. However, the synergistic effect was efficiently abolished by the phosphoinositide 3-kinase (PI3K)/AKT inhibitor LY294002. These results demonstrated that BMP9 may crosstalk with VEGF-a through the PI3K/AKT signaling pathway to induce osteogenic differentiation in MEFs. Thus, our findings demonstrate the effects of VEGF-a on BMP9-induced bone formation and provide a new potential strategy for treating nonunion fractures, large segmental bony defects, and/or osteoporotic fractures.

Download Full-text

Proinflammatory cytokines inhibit osteogenic differentiation from stem cells: implications for bone repair during inflammation

Osteoarthritis and Cartilage ◽

10.1016/j.joca.2008.11.011 ◽

2009 ◽

Vol 17 (6) ◽

pp. 735-742 ◽

Cited By ~ 161

Author(s):

D.C. Lacey ◽

P.J. Simmons ◽

S.E. Graves ◽

J.A. Hamilton

Keyword(s):

Stem Cells ◽

Osteogenic Differentiation ◽

Proinflammatory Cytokines ◽

Bone Repair

Download Full-text

Mineralized collagen scaffolds fabricated with amniotic membrane matrix increase osteogenesis under inflammatory conditions

10.1101/2020.01.23.917443 ◽

2020 ◽

Author(s):

Marley J. Dewey ◽

Eileen M. Johnson ◽

Simona T. Slater ◽

Derek J. Milner ◽

Matthew B. Wheeler ◽

...

Keyword(s):

Osteogenic Differentiation ◽

Amniotic Membrane ◽

Bone Repair ◽

Composite Scaffold ◽

High Energy ◽

Collagen Scaffolds ◽

Membrane Matrix ◽

Inflammatory Conditions ◽

Mineral Deposition ◽

Mineralized Collagen

ABSTRACTDefects in craniofacial bones occur congenitally, after high-energy impacts, and during the course of treatment for stroke and cancer. These injuries are difficult to heal due to the overwhelming size of the injury area and the inflammatory environment surrounding the injury. Significant inflammatory response after injury may greatly inhibit regenerative healing. We have developed mineralized collagen scaffolds that can induce osteogenic differentiation and matrix biosynthesis in the absence of osteogenic media or supplemental proteins. The amniotic membrane is derived from placentas and has been recently investigated as an extracellular matrix to prevent chronic inflammation. Herein, we hypothesized that a mineralized collagen-amnion composite scaffold could increase osteogenic activity in the presence of inflammatory cytokines. We report mechanical properties of a mineralized collagen-amnion scaffold and investigated osteogenic differentiation and mineral deposition of porcine adipose derived stem cells within these scaffolds as a function of inflammatory challenge. Incorporation of amniotic membrane matrix promotes osteogenesis similarly to un-modified mineralized collagen scaffolds, and increases in mineralized collagen-amnion scaffolds under inflammatory challenge. Together, these findings suggest that a mineralized collagen-amnion scaffold may provide a beneficial environment to aid craniomaxillofacial bone repair, especially in the course of defects presenting significant inflammatory complications.

Download Full-text

Human Adipose-Derived Mesenchymal Stem Cells-Incorporated Silk Fibroin as a Potential Bio-Scaffold in Guiding Bone Regeneration

Polymers ◽

10.3390/polym12040853 ◽

2020 ◽

Vol 12 (4) ◽

pp. 853 ◽

Cited By ~ 1

Author(s):

Dewi Sartika ◽

Chih-Hsin Wang ◽

Ding-Han Wang ◽

Juin-Hong Cherng ◽

Shu-Jen Chang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Bone Regeneration ◽

Osteogenic Differentiation ◽

Silk Fibroin ◽

Bone Repair ◽

Matrix Deposition ◽

Calvarial Defects

Recently, stem cell-based bone tissue engineering (BTE) has been recognized as a preferable and clinically significant strategy for bone repair. In this study, a pure 3D silk fibroin (SF) scaffold was fabricated as a BTE material using a lyophilization method. We aimed to investigate the efficacy of the SF scaffold with and without seeded human adipose-derived mesenchymal stem cells (hASCs) in facilitating bone regeneration. The effectiveness of the SF-hASCs scaffold was evaluated based on physical characterization, biocompatibility, osteogenic differentiation in vitro, and bone regeneration in critical rat calvarial defects in vivo. The SF scaffold demonstrated superior biocompatibility and significantly promoted osteogenic differentiation of hASCs in vitro. At six and twelve weeks postimplantation, micro-CT showed no statistical difference in new bone formation amongst all groups. However, histological staining results revealed that the SF-hASCs scaffold exhibited a better bone extracellular matrix deposition in the defect regions compared to other groups. Immunohistochemical staining confirmed this result; expression of osteoblast-related genes (BMP-2, COL1a1, and OCN) with the SF-hASCs scaffold treatment was remarkably positive, indicating their ability to achieve effective bone remodeling. Thus, these findings demonstrate that SF can serve as a potential carrier for stem cells, to be used as an osteoconductive bioscaffold for BTE applications.

Download Full-text

Mettl3 Regulates Osteogenic Differentiation and Alternative Splicing of Vegfa in Bone Marrow Mesenchymal Stem Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20030551 ◽

2019 ◽

Vol 20 (3) ◽

pp. 551 ◽

Cited By ~ 16

Author(s):

Cheng Tian ◽

Yanlan Huang ◽

Qimeng Li ◽

Zhihui Feng ◽

Qiong Xu

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Alternative Splicing ◽

Osteogenic Differentiation ◽

Bone Repair ◽

Bone Mineralization ◽

Sequencing Analysis ◽

Bone Mesenchymal Stem Cells ◽

Vast Number

Bone mesenchymal stem cells (BMSCs) can be a useful cell resource for developing biological treatment strategies for bone repair and regeneration, and their therapeutic applications hinge on an understanding of their physiological characteristics. N6-methyl-adenosine (m6A) is the most prevalent internal chemical modification of mRNAs and has recently been reported to play important roles in cell lineage differentiation and development. However, little is known about the role of m6A modification in the cell differentiation of BMSCs. To address this issue, we investigated the expression of N6-adenosine methyltransferases (Mettl3 and Mettl14) and demethylases (Fto and Alkbh5) and found that Mettl3 was upregulated in BMSCs undergoing osteogenic induction. Furthermore, we knocked down Mettl3 and demonstrated that Mettl3 knockdown decreased the expression of bone formation-related genes, such as Runx2 and Osterix. The alkaline phosphatase (ALP) activity and the formation of mineralized nodules also decreased after Mettl3 knockdown. RNA sequencing analysis revealed that a vast number of genes affected by Mettl3 knockdown were associated with osteogenic differentiation and bone mineralization. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed that the phosphatidylinositol 3-kinase/AKT (PI3K-Akt) signaling pathway appeared to be one of the most enriched pathways, and Western blotting results showed that Akt phosphorylation was significantly reduced after Mettl3 knockdown. Mettl3 has been reported to play an important role in regulating alternative splicing of mRNA in previous research. In this study, we found that Mettl3 knockdown not only reduced the expression of Vegfa but also decreased the level of its splice variants, vegfa-164 and vegfa-188, in Mettl3-deficient BMSCs. These findings might contribute to novel progress in understanding the role of epitranscriptomic regulation in the osteogenic differentiation of BMSCs and provide a promising perspective for new therapeutic strategies for bone regeneration.

Download Full-text