Notch Signaling Augments BMP9-Induced Bone Formation by Promoting the Osteogenesis-Angiogenesis Coupling Process in Mesenchymal Stem Cells (MSCs)

Background/Aims: During bone repair and remodeling, osteogenesis is coupled with angiogenesis. Bone morphogenetic protein (BMP) antagonists are important modulators of BMP signaling and bone homeostasis. Several investigations have demonstrated that one ‘BMP antagonist’, BMP-binding endothelial cell precursor-derived regulator (BMPER), participates in the regulation of BMP signaling. In this study, we examined the role of BMPER in the osteogenesis-angiogenesis coupling process. Methods: Human bone mesenchymal stem cells (hBMSCs) and human umbilical vein endothelial cells (HUVECs) were used in this experiment. After overexpressing or silencing BMPER with lentiviruses or siRNA, hBMSCs were stimulated by BMP-2, and osteogenic differentiation activity was detected by alkaline phosphatase and alizarin red staining. VEGF and endostatin release were assessed by ELISA. HUVEC migration was detected by the cell scratch test and transwell migration assay, and in vitro angiogenesis was determined by the tube formation assay. Bone formation was assessed using in vivo femoral monocortical defect and ectopic bone formation models. Results: BMP-2 upregulated BMPER expression. Overexpression of BMPER remarkably enhanced BMP-2-induced osteogenic differentiation, while suppression of BMPER effectively inhibited this process both in vitro and in vivo. In addition, overexpression of BMPER promoted BMP-2-induced VEGF expression in vitro and vascularization in the ectopic bone formation model. Conclusion: BMPER functions as a positive regulator of the osteogenesis-angiogenesis coupling process in hBMSCs, suggesting a novel therapeutic role of BMPER in the regenerative capacity of bone repair.

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“…Subcutaneous stem cell implantation was performed as previously described [26, 27]. Briefly, BMSCs were infected with different lentiviruses.…”

Section: Methodsmentioning

confidence: 99%

BMPER Enhances Bone Formation by Promoting the Osteogenesis-Angiogenesis Coupling Process in Mesenchymal Stem Cells

Xiao

Wang

Gao

et al. 2018

Cell Physiol Biochem

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“…The GLuc reporters for miR-223 and let-7a-1 were constructed on the base of our recently characterized reporter vector pNRGLuc, which express Gaussia luciferase (GLuc) with a multiple cloning linker at the 3′-end of GLuc coding region [54,55]. As human ARRB1 and LIN28B are well established targets for miR-223 and let-7a-1, which contain miR-223 and let-7a-1-binding sites at their 3′-UTRs, respectively, we PCR amplified the 3′-untranslated sequences of human ARRB1 (or BUTR) and LIN28B, and subcolned them into pNRGLuc vector, resulting in pNRGLuc-BUTR (or GLuc-BUTR) and pNRGLuc-LIN28B (or GLuc-LIN28B), respectively.…”

Section: Construction Of Mir-223 and Let-7a-1 Gaussia Luciferase (Glumentioning

confidence: 99%

A simplified system for the effective expression and delivery of functional mature microRNAs in mammalian cells

et al. 2019

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MicroRNAs (miRNAs) are~22 nucleotide noncoding RNAs that are involved in virtually all aspects of cellular process as their deregulations are associated with many pathological conditions. Mature miRNAs (mMIRs) are generated through a series of tightly-regulated nuclear and cytoplasmic processing events of the transcribed primary, precursor and mMIRs. Effective manipulations of miRNA expression enable us to gain insights into miRNA functions and to explore potential therapeutic applications. Currently, overexpression of miRNAs is achieved by using chemically-synthesized miRNA mimics, or shRNA-like stem-loop vectors to express primary or precursor miRNAs, which are limited by low transfection efficacy or rate-limiting miRNA processing. To overcome rate-limiting miRNA processing, we developed a novel strategy to express mMIRs which are driven by converging U6/H1 dual promoters. As a proof-of-concept study, we constructed mMIR expression vectors for hsa-miR-223 and hsa-Let-7a-1, and demonstrated that the expressed mMIRs effectively silenced target gene expression, specifically suppressed miRNA reporter activity, and significantly affected cell proliferation, similar to respective primary and precursor miRNAs. Furthermore, these mMIR expression vectors can be easily converted into retroviral and adenoviral vectors. Collectively, our simplified mMIR expression system should be a valuable tool to study miRNA functions and/or to deliver miRNA-based therapeutics.

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“…The Notch signalling pathway is involved in cell proliferation, differentiation and apoptosis 69 . In mammals, the Notch signalling pathway contains four Notch receptors, Notch1‐4 and five ligands, Delta‐like (DLL) 1, DLL3, DLL4, Jagged1 and Jagged2 70 . Notch receptors are transmembrane proteins composed of a Notch intracellular domain, transmembrane domain and Notch extracellular domain 71,72 .…”

Section: Factors Involved In Bone Regeneration By Regulating Type H Vmentioning

confidence: 99%

Motivating role of type H vessels in bone regeneration

2020

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Coupling between angiogenesis and osteogenesis has an important role in both normal bone injury repair and successful application of tissue‐engineered bone for bone defect repair. Type H blood vessels are specialized microvascular components that are closely related to the speed of bone healing. Interactions between type H endothelial cells and osteoblasts, and high expression of CD31 and EMCN render the environment surrounding these blood vessels rich in factors conducive to osteogenesis and promote the coupling of angiogenesis and osteogenesis. Type H vessels are mainly distributed in the metaphysis of bone and densely surrounded by Runx2+ and Osterix+ osteoprogenitors. Several other factors, including hypoxia‐inducible factor‐1α, Notch, platelet‐derived growth factor type BB, and slit guidance ligand 3 are involved in the coupling of type H vessel formation and osteogenesis. In this review, we summarize the identification and distribution of type H vessels and describe the mechanism for type H vessel‐mediated modulation of osteogenesis. Type H vessels provide new insights for detection of the molecular and cellular mechanisms that underlie the crosstalk between angiogenesis and osteogenesis. As a result, more feasible therapeutic approaches for treatment of bone defects by targeting type H vessels may be applied in the future.

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Notch Signaling Augments BMP9-Induced Bone Formation by Promoting the Osteogenesis-Angiogenesis Coupling Process in Mesenchymal Stem Cells (MSCs)

Cited by 1,992 publications

References 87 publications

BMPER Enhances Bone Formation by Promoting the Osteogenesis-Angiogenesis Coupling Process in Mesenchymal Stem Cells

BMPER Enhances Bone Formation by Promoting the Osteogenesis-Angiogenesis Coupling Process in Mesenchymal Stem Cells

A simplified system for the effective expression and delivery of functional mature microRNAs in mammalian cells

Motivating role of type H vessels in bone regeneration

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