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Notch Signaling Inhibition by LY411575 Attenuates Osteoblast Differentiation and Decreased Ectopic Bone Formation Capacity of Human Skeletal (Mesenchymal) Stem Cells
Joint Authors
Vishnubalaji, Radhakrishnan
Atteya, Muhammad
Aldahmash, Abdullah
Alajez, Nehad M.
Manikandan, Muthurangan
Alfayez, Musaad
AlMuraikhi, Nihal
Ali, Dalia
Siyal, Abdulaziz
Kassem, Moustapha
Source
Issue
Vol. 2019, Issue 2019 (31 Dec. 2019), pp.1-12, 12 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2019-08-22
Country of Publication
Egypt
No. of Pages
12
Abstract EN
Background.
Chemical biology approaches using small molecule inhibitors targeting specific signaling pathways are useful tools to dissect the molecular mechanisms governing stem cell differentiation and for their possible use in therapeutic interventions.
Methods.
Stem cell signaling small molecule library functional screen was performed employing human bone marrow skeletal (mesenchymal) stem cells (hBMSCs).
Alkaline phosphatase (ALP) activity and formation of mineralized matrix visualized by Alizarin red staining were employed as markers for osteoblastic differentiation.
Global gene expression profiling was conducted using the Agilent microarray platform, and data normalization and bioinformatics were performed using GeneSpring software.
Pathway analyses were conducted using the Ingenuity Pathway Analysis (IPA) tool.
In vivo ectopic bone formation was performed using hBMSC mixed with hydroxyapatite–tricalcium phosphate granules that were implanted subcutaneously in 8-week-old female nude mice.
Hematoxylin and eosin staining and Sirius red staining were performed to identify bone formation in vivo.
Results.
Among the tested molecules, LY411575, a potent γ-secretase and Notch signaling inhibitor, exhibited significant inhibitory effects on osteoblastic differentiation of hBMSCs manifested by reduced ALP activity, mineralized matrix formation, and decreased osteoblast-specific gene expression as well as in vivo ectopic bone formation.
Global gene expression profiling of LY411575-treated cells revealed changes in multiple signaling pathways, including focal adhesion, insulin, TGFβ, IL6, and Notch signaling, and decreased the expression of genes associated with functional categories of tissue development.
Among the affected signaling networks were TGFβ1, SPP1, and ERK regulatory networks.
Conclusions.
We identified γ-secretase inhibitor (LY411575) as a potent regulator of osteoblastic differentiation of hBMSC that may be useful as a therapeutic option for treating conditions associated with ectopic bone formation.
American Psychological Association (APA)
AlMuraikhi, Nihal& Ali, Dalia& Vishnubalaji, Radhakrishnan& Manikandan, Muthurangan& Atteya, Muhammad& Siyal, Abdulaziz…[et al.]. 2019. Notch Signaling Inhibition by LY411575 Attenuates Osteoblast Differentiation and Decreased Ectopic Bone Formation Capacity of Human Skeletal (Mesenchymal) Stem Cells. Stem Cells International،Vol. 2019, no. 2019, pp.1-12.
https://search.emarefa.net/detail/BIM-1208588
Modern Language Association (MLA)
AlMuraikhi, Nihal…[et al.]. Notch Signaling Inhibition by LY411575 Attenuates Osteoblast Differentiation and Decreased Ectopic Bone Formation Capacity of Human Skeletal (Mesenchymal) Stem Cells. Stem Cells International No. 2019 (2019), pp.1-12.
https://search.emarefa.net/detail/BIM-1208588
American Medical Association (AMA)
AlMuraikhi, Nihal& Ali, Dalia& Vishnubalaji, Radhakrishnan& Manikandan, Muthurangan& Atteya, Muhammad& Siyal, Abdulaziz…[et al.]. Notch Signaling Inhibition by LY411575 Attenuates Osteoblast Differentiation and Decreased Ectopic Bone Formation Capacity of Human Skeletal (Mesenchymal) Stem Cells. Stem Cells International. 2019. Vol. 2019, no. 2019, pp.1-12.
https://search.emarefa.net/detail/BIM-1208588
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-1208588