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      Mechanosensing by Gli1 + cells contributes to the orthodontic force‐induced bone remodelling

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          Abstract

          Objectives

          Gli1 + cells have received extensive attention in tissue homeostasis and injury mobilization. The aim of this study was to investigate whether Gli1 + cells respond to force and contribute to bone remodelling.

          Materials and methods

          We established orthodontic tooth movement (OTM) model to assess the bone response for mechanical force. The transgenic mice were utilized to label and inhibit Gli1 + cells, respectively. Additionally, mice that conditional ablate Yes‐associated protein (Yap) in Gli1 + cells were applied in the present study. The tooth movement and bone remodelling were analysed.

          Results

          We first found Gli1 + cells expressed in periodontal ligament (PDL). They were proliferated and differentiated into osteoblastic cells under tensile force. Next, both pharmacological and genetic Gli1 inhibition models were utilized to confirm that inhibition of Gli1 + cells led to arrest of bone remodelling. Furthermore, immunofluorescence staining identified classical mechanotransduction factor Yap expressed in Gli1 + cells and decreased after suppression of Gli1 + cells. Additionally, conditional ablation of Yap gene in Gli1 + cells inhibited the bone remodelling as well, suggesting Gli1 + cells are force‐responsive cells.

          Conclusions

          Our findings highlighted that Gli1 + cells in PDL directly respond to orthodontic force and further mediate bone remodelling, thus providing novel functional evidence in the mechanism of bone remodelling and first uncovering the mechanical responsive property of Gli1 + cells.

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          Most cited references33

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          Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists.

          The developmentally important Hedgehog (Hh) signaling pathway has recently been implicated in several forms of solid cancer. Current drug development programs focus on targeting the protooncogene Smoothened, a key transmembrane pathway member. These drug candidates, albeit promising, do not address the scenario in which pathway activation occurs downstream of Smoothened, as observed in cases of medulloblastoma, glioma, pericytoma, breast cancer, and prostate cancer. A cellular screen for small-molecule antagonists of GLI-mediated transcription, which constitutes the final step in the Hh pathway, revealed two molecules that are able to selectively inhibit GLI-mediated gene transactivation. We provide genetic evidence of downstream pathway blockade by these compounds and demonstrate the ineffectiveness of upstream antagonists such as cyclopamine in such situations. Mechanistically, both inhibitors act in the nucleus to block GLI function, and one of them interferes with GLI1 DNA binding in living cells. Importantly, the discovered compounds efficiently inhibited in vitro tumor cell proliferation in a GLI-dependent manner and successfully blocked cell growth in an in vivo xenograft model using human prostate cancer cells harboring downstream activation of the Hh pathway.
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            Gli1(+) Mesenchymal Stromal Cells Are a Key Driver of Bone Marrow Fibrosis and an Important Cellular Therapeutic Target.

            Bone marrow fibrosis (BMF) develops in various hematological and non-hematological conditions and is a central pathological feature of myelofibrosis. Effective cell-targeted therapeutics are needed, but the cellular origin of BMF remains elusive. Here, we show using genetic fate tracing in two murine models of BMF that Gli1(+) mesenchymal stromal cells (MSCs) are recruited from the endosteal and perivascular niche to become fibrosis-driving myofibroblasts in the bone marrow. Genetic ablation of Gli1(+) cells abolished BMF and rescued bone marrow failure. Pharmacological targeting of Gli proteins with GANT61 inhibited Gli1(+) cell expansion and myofibroblast differentiation and attenuated fibrosis severity. The same pathway is also active in human BMF, and Gli1 expression in BMF significantly correlates with the severity of the disease. In addition, GANT61 treatment reduced the myofibroblastic phenotype of human MSCs isolated from patients with BMF, suggesting that targeting of Gli proteins could be a relevant therapeutic strategy.
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              Sox2+ stem cells contribute to all epithelial lineages of the tooth via Sfrp5+ progenitors.

              The continuously growing mouse incisor serves as a valuable model to study stem cell regulation during organ renewal. Epithelial stem cells are localized in the proximal end of the incisor in the labial cervical loop. Here, we show that the transcription factor Sox2 is a specific marker for these stem cells. Sox2+ cells became restricted to the labial cervical loop during tooth morphogenesis, and they contributed to the renewal of enamel-producing ameloblasts as well as all other epithelial cell lineages of the tooth. The early progeny of Sox2-positive stem cells transiently expressed the Wnt inhibitor Sfrp5. Sox2 expression was regulated by the tooth initiation marker FGF8 and specific miRNAs, suggesting a fine-tuning to maintain homeostasis of the dental epithelium. The identification of Sox2 as a marker for the dental epithelial stem cells will facilitate further studies on their lineage segregation and differentiation during tooth renewal. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                chenghu@xiterm.com
                jinfang@fmmu.edu.cn
                Journal
                Cell Prolif
                Cell Prolif
                10.1111/(ISSN)1365-2184
                CPR
                Cell Proliferation
                John Wiley and Sons Inc. (Hoboken )
                0960-7722
                1365-2184
                23 April 2020
                May 2020
                : 53
                : 5 ( doiID: 10.1111/cpr.v53.5 )
                : e12810
                Affiliations
                [ 1 ] State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases Center for Tissue Engineering School of Stomatology The Fourth Military Medical University Xi’an China
                [ 2 ] Xi’an Institute of Tissue Engineering and Regenerative Medicine Xi’an China
                [ 3 ] Department of Orthodontic Dentistry School of Stomatology The Fourth Military Medical University Xi’an China
                [ 4 ] Department of Oral Implantology School of Stomatology The Fourth Military Medical University Xi’an China
                Author notes
                [*] [* ] Correspondence

                Cheng‐Hu Hu and Fang Jin, State Key Laboratory of Military Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi 710032, China.

                Emails: chenghu@ 123456xiterm.com (CHH); jinfang@ 123456fmmu.edu.cn (YF)

                Author information
                https://orcid.org/0000-0002-2586-1152
                https://orcid.org/0000-0003-2443-6485
                Article
                CPR12810
                10.1111/cpr.12810
                7260067
                32472648
                6484296a-58bf-448d-a7a6-403e2dafc34c
                © 2020 The Authors. Cell Proliferation published by John Wiley & Sons Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 11 February 2020
                : 13 March 2020
                : 25 March 2020
                Page count
                Figures: 9, Tables: 0, Pages: 16, Words: 8247
                Funding
                Funded by: General Program of China Postdoctoral Science Foundation
                Award ID: to B.S.
                Funded by: grants from The National Natural Science Foundation of China
                Award ID: 81930025
                Funded by: The National Key Research and Development Program of China
                Award ID: 2016YFC1102900
                Funded by: The Postdoctoral Innovative Talents Support Program of China
                Award ID: BX20190380 to B.S.
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                May 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.3 mode:remove_FC converted:29.05.2020

                Cell biology
                bone remodelling,gli1,mechanical force,orthodontic tooth movement
                Cell biology
                bone remodelling, gli1, mechanical force, orthodontic tooth movement

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