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

Background/Aims: Mesenchymal stem cells (MSCs) are multipotent progenitors that can differentiate into several lineages including bone. Successful bone formation requires osteogenesis and angiogenesis coupling of MSCs. Here, we investigate if simultaneous activation of BMP9 and Notch signaling yields effective osteogenesis-angiogenesis coupling in MSCs. Methods: Recently-characterized immortalized mouse adipose-derived progenitors (iMADs) were used as MSC source. Transgenes BMP9, NICD and dnNotch1 were expressed by adenoviral vectors. Gene expression was determined by qPCR and immunohistochem¡stry. Osteogenic activity was assessed by in vitro assays and in vivo ectopic bone formation model. Results: BMP9 upregulated expression of Notch receptors and ligands in iMADs. Constitutively-active form of Notch1 NICD1 enhanced BMP9-induced osteogenic differentiation both in vitro and in vivo, which was effectively inhibited by dominant-negative form of Notch1 dnNotch1. BMP9- and NICD1-transduced MSCs implanted with a biocompatible scaffold yielded highly mature bone with extensive vascularization. NICD1 enhanced BMP9-induced expression of key angiogenic regulators in iMADs and Vegfa in ectopic bone, which was blunted by dnNotch1. Conclusion: Notch signaling may play an important role in BMP9-induced osteogenesis and angiogenesis. It’s conceivable that simultaneous activation of the BMP9 and Notch pathways should efficiently couple osteogenesis and angiogenesis of MSCs for successful bone tissue engineering.

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Canonical Wnts function as potent regulators of osteogenesis by human mesenchymal stem cells

The Journal of Cell Biology ◽

10.1083/jcb.200810137 ◽

2009 ◽

Vol 185 (1) ◽

pp. 67-75 ◽

Cited By ~ 102

Author(s):

Guizhong Liu ◽

Sapna Vijayakumar ◽

Luca Grumolato ◽

Randy Arroyave ◽

HuiFang Qiao ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Bone Formation ◽

Wnt Signaling ◽

De Novo ◽

Human Mesenchymal Stem Cells ◽

Mitogen Activated Protein Kinase ◽

Bone Homeostasis

Genetic evidence indicates that Wnt signaling is critically involved in bone homeostasis. In this study, we investigated the functions of canonical Wnts on differentiation of adult multipotent human mesenchymal stem cells (hMSCs) in vitro and in vivo. We observe differential sensitivities of hMSCs to Wnt inhibition of osteogenesis versus adipogenesis, which favors osteoblastic commitment under binary in vitro differentiation conditions. Wnt inhibition of osteogenesis is associated with decreased expression of osteoblastic transcription factors and inhibition of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase activation, which are involved in osteogenic differentiation. An hMSC subpopulation exhibits high endogenous Wnt signaling, the inhibition of which enhances osteogenic and adipogenic differentiation in vitro. In an in vivo bone formation model, high levels of Wnt signaling inhibit de novo bone formation by hMSCs. However, hMSCs with exogenous expression of Wnt1 but not stabilized β-catenin markedly stimulate bone formation by naive hMSCs, arguing for an important role of a canonical Wnt gradient in hMSC osteogenesis in vivo.

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In vivo bioluminescence imaging study to monitor ectopic bone formation by luciferase gene marked mesenchymal stem cells

Journal of Orthopaedic Research® ◽

10.1002/jor.20582 ◽

2008 ◽

Vol 26 (7) ◽

pp. 901-909 ◽

Cited By ~ 31

Author(s):

Cristina Olivo ◽

Jacqueline Alblas ◽

Vivienne Verweij ◽

Anton-Jan Van Zonneveld ◽

Wouter J. A. Dhert ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Bone Formation ◽

Bioluminescence Imaging ◽

Imaging Study ◽

Ectopic Bone Formation ◽

Luciferase Gene ◽

Ectopic Bone ◽

In Vivo Bioluminescence Imaging

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Alginate Bead-Encapsulated PEDF Induces Ectopic Bone Formation In Vivo in the Absence of Co-Administered Mesenchymal Stem Cells

Current Drug Targets ◽

10.2174/1389450116666151001112455 ◽

2018 ◽

Vol 19 (5) ◽

pp. 467-478 ◽

Cited By ~ 4

Author(s):

Mina Elahy ◽

Michael R. Doschak ◽

Jeffery D. Hughes ◽

Swati Baindur-Hudson ◽

Crispin R. Dass

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Bone Formation ◽

Alginate Bead ◽

Ectopic Bone Formation ◽

Ectopic Bone

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Faculty Opinions recommendation of cAMP/PKA pathway activation in human mesenchymal stem cells in vitro results in robust bone formation in vivo.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1111087.567057 ◽

2008 ◽

Author(s):

Anthony Ratcliffe

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Bone Formation ◽

Human Mesenchymal Stem Cells ◽

Pathway Activation ◽

Pka Pathway

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Activation of the cAMP/PKA pathway in human mesenchymal stem cells in vitro results in robust bone formation in vivo

Bone ◽

10.1016/j.bone.2007.12.042 ◽

2008 ◽

Vol 42 ◽

pp. S30

Author(s):

R. Siddappa ◽

J. Doorn ◽

A. Leusink ◽

C. van Blitterswijk ◽

J. de Boer

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Bone Formation ◽

Human Mesenchymal Stem Cells ◽

Pka Pathway

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Pyridoxal-5′-Phosphate Promotes Immunomodulatory Function of Adipose-Derived Mesenchymal Stem Cells through Indoleamine 2,3-Dioxygenase-1 and TLR4/NF-κB Pathway

Stem Cells International ◽

10.1155/2019/3121246 ◽

2019 ◽

Vol 2019 ◽

pp. 1-15

Author(s):

Cong Li ◽

Jinxian Huang ◽

Huasu Zhu ◽

Qing Shi ◽

Dong Li ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Active Form ◽

Inhibitory Effect ◽

Cytokine Secretion ◽

Regulatory Function ◽

Surface Receptors ◽

T Lymphocyte Proliferation

Adipose-derived mesenchymal stem cells (A-MSCs) are promising cellular therapies for the treatment of immune-mediated diseases. Non-gene editing technologies can improve the immune regulatory function of A-MSCs. Our preliminary experiments revealed that an active form of vitamin B6—pyridoxal-5′-phosphate (PLP)—plays an important role in regulating gene expression and cytokine secretion in A-MSCs in vivo. To further clarify the effect of PLP on receptors and cytokines related to the immune regulatory function of A-MSCs, a series of experiments were designed to verify the relationships between PLP and A-MSCs in vitro. Initially, A-MSCs were obtained, and cytokine secretion and the expression of IDO1, NF-κB, and Toll-like receptors in PLP-stimulated A-MSCs were evaluated. In addition, coculture was used to detect A-MSCs-mediated apoptosis of CD3+CD8+ T lymphocytes. These results showed that A-MSCs stimulated with PLP were highly proliferative, consistent with their pluripotent capacity. Further, the surface receptors TLR3, TLR4, IDO1, and NF-κB were upregulated, while TLR6 was downregulated. Concurrently, A-MSCs preconditioned with PLP had the greatest inhibitory effect on CD3+CD8+ T lymphocyte proliferation, indicating that PLP altered the immune regulatory function of A-MSCs through the regulation of TLRs and IDO1 expression.

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

Cellular Physiology and Biochemistry ◽

10.1159/000487969 ◽

2018 ◽

Vol 45 (5) ◽

pp. 1927-1939 ◽

Cited By ~ 6

Author(s):

Fei Xiao ◽

Chuandong Wang ◽

Chenglong Wang ◽

Yuan Gao ◽

Xiaoling Zhang ◽

...

Keyword(s):

Stem Cells ◽

Bone Formation ◽

Bone Repair ◽

Ectopic Bone Formation ◽

Bmp Signaling ◽

Coupling Process ◽

Ectopic Bone

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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Strontium folic acid derivative functionalized titanium surfaces for enhanced osteogenic differentiation of mesenchymal stem cells in vitro and bone formation in vivo

Journal of Materials Chemistry B ◽

10.1039/c7tb01529a ◽

2017 ◽

Vol 5 (33) ◽

pp. 6811-6826 ◽

Cited By ~ 14

Author(s):

Kui Xu ◽

Weizhen Chen ◽

Caiyun Mu ◽

Yonglin Yu ◽

Kaiyong Cai

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Folic Acid ◽

Bone Formation ◽

Osteogenic Differentiation ◽

Acid Derivative ◽

Titanium Surfaces

Strontium folic acid derivative (FASr) functionalized titanium surfaces improve the in vitro osteogenic differentiation of MSCs and osseointegration in vivo.

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