scholarly journals The osteogenic potential of the neural crest lineage may contribute to craniosynostosis

2018 ◽  
Author(s):  
Daniel Doro ◽  
Annie Liu ◽  
Agamemnon E Grigoriadis ◽  
Karen J Liu
Keyword(s):  
Neural Crest ◽  
Mouse Models ◽  
Dura Mater ◽  
Osteogenic Potential ◽  
Cranial Sutures ◽  
Craniofacial Skeleton ◽  
Primary Driver ◽  
Parietal Bones ◽  
Do So

AbstractThe craniofacial skeleton is formed from the neural crest and mesodermal lineages, both of which contribute mesenchymal precursors during formation of the skull bones. The large majority of cranial sutures also include a proportion of neural crest derived mesenchyme. While some studies have addressed the relative healing abilities of neural crest and mesodermal bone, relatively little attention has been paid to differences in intrinsic osteogenic potential. Here we use mouse models to compare neural crest osteoblasts (from frontal bones or dura mater) to mesodermal osteoblasts (from parietal bones). Using in vitro culture approaches we find that neural crest-derived osteoblasts readily generate bony nodules while mesodermal osteoblasts do so less efficiently. Furthermore, we find that co-culture of neural crest-derived osteoblasts with mesodermal osteoblasts is sufficient to nucleate ossification centres. All together, this suggests that the intrinsic osteogenic abilities of neural crest-derived mesenchyme may be a primary driver behind craniosynostosis.

Dura Mater Maintains Rat Cranial Sutures in Vitro by Regulating Suture Cell Proliferation and Collagen Production

1999 ◽  
Vol 10 (2) ◽  
pp. 169
Author(s):  
L. A. Opperman ◽  
A Chhabra ◽  
A. A. Nolen ◽  
Y. Bao ◽  
R. C. Ogle
Keyword(s):  
Cell Proliferation ◽  
Dura Mater ◽  
Cranial Sutures ◽  
Collagen Production

scholarly journals Pharmacological targeting of KDM6A and KDM6B, as a novel therapeutic strategy for treating craniosynostosis in Saethre-Chotzen syndrome

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Clara Pribadi ◽  
Esther Camp ◽  
Dimitrios Cakouros ◽  
Peter Anderson ◽  
Carlotta Glackin ◽  
...  
Keyword(s):  
Osteogenic Differentiation ◽  
Progenitor Cells ◽  
Therapeutic Strategy ◽  
In Vivo Studies ◽  
Osteogenic Potential ◽  
Cranial Sutures ◽  
Mesenchymal Progenitor Cells ◽  
Suture Fusion ◽  
Twist 1

Abstract Background During development, excessive osteogenic differentiation of mesenchymal progenitor cells (MPC) within the cranial sutures can lead to premature suture fusion or craniosynostosis, leading to craniofacial and cognitive issues. Saethre-Chotzen syndrome (SCS) is a common form of craniosynostosis, caused by TWIST-1 gene mutations. Currently, the only treatment option for craniosynostosis involves multiple invasive cranial surgeries, which can lead to serious complications. Methods The present study utilized Twist-1 haploinsufficient (Twist-1del/+) mice as SCS mouse model to investigate the inhibition of Kdm6a and Kdm6b activity using the pharmacological inhibitor, GSK-J4, on calvarial cell osteogenic potential. Results This study showed that the histone methyltransferase EZH2, an osteogenesis inhibitor, is downregulated in calvarial cells derived from Twist-1del/+ mice, whereas the counter histone demethylases, Kdm6a and Kdm6b, known promoters of osteogenesis, were upregulated. In vitro studies confirmed that siRNA-mediated inhibition of Kdm6a and Kdm6b expression suppressed osteogenic differentiation of Twist-1del/+ calvarial cells. Moreover, pharmacological targeting of Kdm6a and Kdm6b activity, with the inhibitor, GSK-J4, caused a dose-dependent suppression of osteogenic differentiation by Twist-1del/+ calvarial cells in vitro and reduced mineralized bone formation in Twist-1del/+ calvarial explant cultures. Chromatin immunoprecipitation and Western blot analyses found that GSK-J4 treatment elevated the levels of the Kdm6a and Kdm6b epigenetic target, the repressive mark of tri-methylated lysine 27 on histone 3, on osteogenic genes leading to repression of Runx2 and Alkaline Phosphatase expression. Pre-clinical in vivo studies showed that local administration of GSK-J4 to the calvaria of Twist-1del/+ mice prevented premature suture fusion and kept the sutures open up to postnatal day 20. Conclusion The inhibition of Kdm6a and Kdm6b activity by GSK-J4 could be used as a potential non-invasive therapeutic strategy for preventing craniosynostosis in children with SCS. Graphical abstract Pharmacological targeting of Kdm6a/b activity can alleviate craniosynostosis in Saethre-Chotzen syndrome. Aberrant osteogenesis by Twist-1 mutant cranial suture mesenchymal progenitor cells occurs via deregulation of epigenetic modifiers Ezh2 and Kdm6a/Kdm6b. Suppression of Kdm6a- and Kdm6b-mediated osteogenesis with GSK-J4 inhibitor can prevent prefusion of cranial sutures.

scholarly journals An Evolutionary Conserved Signaling Network Between Mouse and Human Underlies the Differential Osteoskeletal Potential of Frontal and Parietal Calvarial Bones

2021 ◽  
Vol 12 ◽  
Author(s):  
Siddharth Menon ◽  
Julika Huber ◽  
Chris Duldulao ◽  
Michael T. Longaker ◽  
Natalina Quarto
Keyword(s):  
Mouse Models ◽  
Regional Differences ◽  
Molecular Level ◽  
Mammalian Species ◽  
Osteogenic Potential ◽  
Differential Signaling ◽  
Translational Studies ◽  
Canonical Wnt

The mammalian calvarial vault is an ancient and highly conserved structure among species, however, the mechanisms governing osteogenesis of the calvarial vault and how they might be conserved across mammalian species remain unclear. The aim of this study was to determine if regional differences in osteogenic potential of the calvarial vault, first described in mice, extend to humans. We derived human frontal and parietal osteoblasts from fetal calvarial tissue, demonstrating enhanced osteogenic potential both in vitro and in vivo of human frontal derived osteoblasts compared to parietal derived osteoblasts. Furthermore, we found shared differential signaling patterns in the canonical WNT, TGF-β, BMP, and FGF pathways previously described in the mouse to govern these regional differences in osteogenic potential. Taken together, our findings unveil evolutionary conserved similarities both at functional and molecular level between the mouse and human calvarial bones, providing further support that studies employing mouse models, are suitable for translational studies to human.

Cranial sutures require tissue interactions with dura mater to resist osseous obliteration in vitro

2009 ◽  
Vol 10 (12) ◽  
pp. 1978-1987 ◽  
Author(s):  
Lynne A. Opperman ◽  
Ralph W. Passarelli ◽  
Ellen P. Morgan ◽  
Mark Reintjes ◽  
Roy C. Ogle
Keyword(s):  
Dura Mater ◽  
Cranial Sutures ◽  
Tissue Interactions

In vitro effect of prolactin on the osteogenic potential of bone marrow mesenchymal stem cells of rats

2013 ◽  
Author(s):  
Melo Ocarino Natalia de ◽  
Silvia Silva Santos ◽  
Lorena Rocha ◽  
Juneo Freitas ◽  
Reis Amanda Maria Sena ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Osteogenic Potential ◽  
Marrow Mesenchymal Stem Cells ◽  
Vitro Effect

Induction of melanocyte precursors from neural crest cells surrounding the neural tube-like structures developed in vitro using mouse ES cell culture

2007 ◽  
Vol 27 (1) ◽  
pp. 45-52
Author(s):  
Koh-ichi Atoh ◽  
Manae S. Kurokawa ◽  
Hideshi Yoshikawa ◽  
Chieko Masuda ◽  
Erika Takada ◽  
...  
Keyword(s):  
Cell Culture ◽  
Neural Crest ◽  
Neural Tube ◽  
Neural Crest Cells ◽  
Es Cell ◽  
Mouse Es Cell

scholarly journals Restoration of Osteogenesis by CRISPR/Cas9 Genome Editing of the Mutated COL1A1 Gene in Osteogenesis Imperfecta

2021 ◽  
Vol 10 (14) ◽  
pp. 3141
Author(s):  
Hyerin Jung ◽  
Yeri Alice Rim ◽  
Narae Park ◽  
Yoojun Nam ◽  
Ji Hyeon Ju
Keyword(s):  
Osteogenesis Imperfecta ◽  
Type I Collagen ◽  
Disease Modeling ◽  
Bone Fragility ◽  
Osteogenic Potential ◽  
Type I ◽  
Gene Correction ◽  
Col1a1 Gene ◽  
Collagen Formation

Osteogenesis imperfecta (OI) is a genetic disease characterized by bone fragility and repeated fractures. The bone fragility associated with OI is caused by a defect in collagen formation due to mutation of COL1A1 or COL1A2. Current strategies for treating OI are not curative. In this study, we generated induced pluripotent stem cells (iPSCs) from OI patient-derived blood cells harboring a mutation in the COL1A1 gene. Osteoblast (OB) differentiated from OI-iPSCs showed abnormally decreased levels of type I collagen and osteogenic differentiation ability. Gene correction of the COL1A1 gene using CRISPR/Cas9 recovered the decreased type I collagen expression in OBs differentiated from OI-iPSCs. The osteogenic potential of OI-iPSCs was also recovered by the gene correction. This study suggests a new possibility of treatment and in vitro disease modeling using patient-derived iPSCs and gene editing with CRISPR/Cas9.

627 The DLL3-targeted half-life extended bispecific T cell engager (HLE BiTE®) immune-oncology therapy AMG 757 has potent antitumor activity in neuroendocrine cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A663-A663
Author(s):  
Keegan Cooke ◽  
Juan Estrada ◽  
Jinghui Zhan ◽  
Jonathan Werner ◽  
Fei Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Mouse Models ◽  
T Cell Activation ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Human T Cells

BackgroundNeuroendocrine tumors (NET), including small cell lung cancer (SCLC), have poor prognosis and limited therapeutic options. AMG 757 is an HLE BiTE® immune therapy designed to redirect T cell cytotoxicity to NET cells by binding to Delta-like ligand 3 (DLL3) expressed on the tumor cell surface and CD3 on T cells.MethodsWe evaluated activity of AMG 757 in NET cells in vitro and in mouse models of neuroendocrine cancer in vivo. In vitro, co-cultures of NET cells and human T cells were treated with AMG 757 in a concentration range and T cell activation, cytokine production, and tumor cell killing were assessed. In vivo, AMG 757 antitumor efficacy was evaluated in xenograft NET and in orthotopic models designed to mimic primary and metastatic SCLC lesions. NSG mice bearing established NET were administered human T cells and then treated once weekly with AMG 757 or control HLE BiTE molecule; tumor growth inhibition was assessed. Pharmacodynamic effects of AMG 757 in tumors were also evaluated in SCLC models following a single administration of human T cells and AMG 757 or control HLE BiTE molecule.ResultsAMG 757 induced T cell activation, cytokine production, and potent T cell redirected killing of DLL3-expressing SCLC, neuroendocrine prostate cancer, and other DLL3-expressing NET cell lines in vitro. AMG 757-mediated redirected lysis was specific for DLL3-expressing cells. In patient-derived xenograft and orthotopic models of SCLC, single-dose AMG 757 effectively engaged human T cells administered systemically, leading to a significant increase in the number of human CD4+ and CD8+ T cells in primary and metastatic tumor lesions. Weekly administration of AMG 757 induced significant tumor growth inhibition of SCLC (figure 1) and other NET, including complete regression of established tumors and clearance of metastatic lesions. These findings warranted evaluation of AMG 757 (NCT03319940); the phase 1 study includes dose exploration (monotherapy and in combination with pembrolizumab) and dose expansion (monotherapy) in patients with SCLC (figure 2). A study of AMG 757 in patients with neuroendocrine prostate cancer is under development based on emerging data from the ongoing phase 1 study.Abstract 627 Figure 1AMG 757 Significantly reduced tumor growth in orthotopic SCLC mouse modelsAbstract 627 Figure 2AMG 757 Phase 1 study designConclusionsAMG 757 engages and activates T cells to kill DLL3-expressing SCLC and other NET cells in vitro and induces significant antitumor activity against established xenograft tumors in mouse models. These preclinical data support evaluation of AMG 757 in clinical studies of patients with NET.Ethics ApprovalAll in vivo work was conducted under IACUC-approved protocol #2009-00046.

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