Neural EGF-like protein 1 (NELL-1): Signaling crosstalk in mesenchymal stem cells and applications in regenerative medicine

Pakvasa, Mikhail; Alverdy, Alex; Mostafa, Sami; Wang, Eric; Fu, Lucy; Li, Alexander; Oliveira, Leonardo P.; Athiviraham, Aravind; Lee, Michael J.; Wolf, Jennifer Moriatis; He, Tong Chuan; Reid, Russell R.

doi:10.1016/j.gendis.2017.07.006

Cited by 30 publications

(24 citation statements)

References 133 publications

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“…Studies have shown the multi-differentiation potentials of OAT-PFs as MSC [54]. Our work suggests that OAT-produced growth factors interacting with multiple signaling pathways (TGFβ/Wnt/Ca+/FGF/Notch/MAPK/PI3K) that support repair mechanisms such as adipogenesis, osteogenesis, myogenesis, chondrogenesis, neurogenesis and angiogenesis [31][32][33][37][38][39][40][41][42][43][44][45][46]. Furthermore, we have demonstrated a depot specific triglyceride composition of OAT, for example, stearic acid (18:0 FA), a stable waxy solid fat.…”

Section: Speculations From Current Studymentioning

confidence: 68%

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Distinctive Features of Orbital Adipose Tissue (OAT) in Graves’ Orbitopathy

Zhang

Evans

Ruhland

et al. 2020

IJMS

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Depot specific expansion of orbital-adipose-tissue (OAT) in Graves’ Orbitopathy (GO) is associated with lipid metabolism signaling defects. We hypothesize that the unique adipocyte biology of OAT facilitates its expansion in GO. A comprehensive comparison of OAT and white-adipose-tissue (WAT) was performed by light/electron-microscopy, lipidomic and transcriptional analysis using ex vivo WAT, healthy OAT (OAT-H) and OAT from GO (OAT-GO). OAT-H/OAT-GO have a single lipid-vacuole and low mitochondrial number. Lower lipolytic activity and smaller adipocytes of OAT-H/OAT-GO, accompanied by similar essential linoleic fatty acid (FA) and (low) FA synthesis to WAT, revealed a hyperplastic OAT expansion through external FA-uptake via abundant SLC27A6 (FA-transporter) expression. Mitochondrial dysfunction of OAT in GO was apparent, as evidenced by the increased mRNA expression of uncoupling protein 1 (UCP1) and mitofusin-2 (MFN2) in OAT-GO compared to OAT-H. Transcriptional profiles of OAT-H revealed high expression of Iroquois homeobox-family (IRX-3&5), and low expression in HOX-family/TBX5 (essential for WAT/BAT (brown-adipose-tissue)/BRITE (BRown-in-whITE) development). We demonstrated unique features of OAT not presented in either WAT or BAT/BRITE. This study reveals that the pathologically enhanced FA-uptake driven hyperplastic expansion of OAT in GO is associated with a depot specific mechanism (the SLC27A6 FA-transporter) and mitochondrial dysfunction. We uncovered that OAT functions as a distinctive fat depot, providing novel insights into adipocyte biology and the pathological development of OAT expansion in GO.

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Section: Speculations From Current Studymentioning

confidence: 68%

“…Angiopoietin (ANGPT4) [39] angiogenesis Osteoglycin (OGN) [40] bone formation Neural EGF-like protein (NELL1) [41] bone formation TGFβ family 1 [42] (TGFB2, BMP3, 7,11) and Latent TGFβ binding protein 1…”

Section: Up-regulated Growth Factor (Multi-function 1) Known Functionmentioning

confidence: 99%

Distinctive Features of Orbital Adipose Tissue (OAT) in Graves’ Orbitopathy

Zhang

Evans

Ruhland

et al. 2020

IJMS

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“…The effect of Nell-1 gene on osteogenesis has been verified through in vivo and in vitro study, but the mechanism of Nell-1’s function on BMSCs remains unclear. Studies suggested that Nell-1 protein acted on various signaling pathway including Wnt signaling pathway, hedgehog signaling pathway, and BMP2 signaling pathway ( Shen et al, 2016 ; Pakvasa et al, 2017 ; Li et al, 2018 ). Zhang found that Nell-1 protein induced phosphorylation of Runx2 ( Zhang et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

Activation of Nell-1 in BMSC Sheet Promotes Implant Osseointegration Through Regulating Runx2/Osterix Axis

Lai

et al. 2020

Front. Cell Dev. Biol.

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Neural epidermal growth factor-like 1 protein (Nell-1) is first studied because of its association with human craniosynostosis. Nell-1 has been used to accelerate the process of fracture healing because of the osteoinductive ability in recent years. However, the role of Nell-1 during the process of osteointegration is unknown. Here we show that activation of Nell-1 in the BMSC sheet promotes osseointegration in vivo and in vitro. We found that overexpression of Nell-1 improved osteogenic differentiation and enhanced matrix mineralization of BMSCs through increasing expression of Runx2 and Osterix. Activation of Nell-1 up-regulated the expression ratio of OPG/RANKL, which might have a negative influence on osteoclast differentiation. Furthermore, we obtained BMSC sheet-implant complexes transfected with lentivirus overexpressing and interfering Nell-1 in in vivo study, and confirmed that overexpression of Nell-1 promoted new bone formation around the implant and increased the bone-implant contacting area percentage. Our results demonstrate that activation of Nell-1 improves implant osteointegration by regulating Runx2/Osterix axis and shows the potential of BMSC sheet-implant complexes in gene therapy.

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“…It is proposed integrinβ1 protein can mediate cell adhesion and integrate signals from a variety of cytokines and other growth factor. NELL-1(potent osteo-inductive factor) binding to integrinβ1 activates an intracellular signaling cascade that promotes cell adhesion, proliferation, and osteogenic differentiation 72. It can be seen that the expression of both integrinβ1 and vinculin manifested more abundant expression (much stronger fluorescent intensity) on the (GO-CS)20 scaffold in comparison to the pure PU scaffold after 4 h of culturing.The much stronger fluorescent intensity of integrinβ1 and vinculin expression on (GO-CS)20scaffold suggest the coated scaffold shows stronger cell adhesion, which indicate (GO-CS)20 scaffold holds stronger potential for tissue regeneration than the PU control sample 72.…”

mentioning

confidence: 99%

“…NELL-1(potent osteo-inductive factor) binding to integrinβ1 activates an intracellular signaling cascade that promotes cell adhesion, proliferation, and osteogenic differentiation 72. It can be seen that the expression of both integrinβ1 and vinculin manifested more abundant expression (much stronger fluorescent intensity) on the (GO-CS)20 scaffold in comparison to the pure PU scaffold after 4 h of culturing.The much stronger fluorescent intensity of integrinβ1 and vinculin expression on (GO-CS)20scaffold suggest the coated scaffold shows stronger cell adhesion, which indicate (GO-CS)20 scaffold holds stronger potential for tissue regeneration than the PU control sample 72. CCK-8 assay proliferation after 1, 3 and 5 days of culture, n=5 per group; (*), p < 0.05 when compared with blank group, (#), p < 0.05 when compared with PU control group.The proliferation of cells was qualitatively determined by CCK-8 assay, seeFigure 10.…”

mentioning

confidence: 99%

Tissue Scaffolds with Nanoscale Hybrid Coating Shining New Lights on Multi-Modal Bone Targeted Therapeutics

Guo¹,

Jiang²,

moore³

et al. 2019

Preprint

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<p>The challenging post-surgery management of bone metastasis sees the needs for multi-functional bone scaffolds that offer multi-modal therapeutic functions. Through a nature-inspired layer-by-layer assembly process, we developed a unique multi-functional tissue scaffold that consists of porous polyurethane substrate and nanoscale chitosan/ graphene oxide hybrid coating. Alternative layers of drug laden chitosan and graphene oxide nanosheets were held together through strong electrostatic interaction, giving rise to a robust multilayer architecture with control over structural element orientation and chemical composition at nanoscale. For the first time, proof-of-concept on combining pH-controlled co-delivery of multiple therapeutic agents and photothermal therapy have demonstrated, in the context of malignant bone cancer treatment. Our scaffold system can be tailored to the patient’s specific needs through loading of bespoke therapeutic agents and offering on-demand photothermal therapy. The methodology can also be generalized to create functional surfaces for a wide range of biomedical devices as well as for applications beyond healthcare technology.</p>

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Neural EGF-like protein 1 (NELL-1): Signaling crosstalk in mesenchymal stem cells and applications in regenerative medicine

Cited by 30 publications

References 133 publications

Distinctive Features of Orbital Adipose Tissue (OAT) in Graves’ Orbitopathy

Distinctive Features of Orbital Adipose Tissue (OAT) in Graves’ Orbitopathy

Activation of Nell-1 in BMSC Sheet Promotes Implant Osseointegration Through Regulating Runx2/Osterix Axis

Tissue Scaffolds with Nanoscale Hybrid Coating Shining New Lights on Multi-Modal Bone Targeted Therapeutics

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