Publication: Gli1<sup>+</sup> Mesenchymal Stromal Cells Are a Key Driver of Bone Marrow Fibrosis and an Important Cellular Therapeutic Target
Issued Date
2017-06-01
Resource Type
ISSN
18759777
19345909
19345909
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2-s2.0-85018173491
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Mahidol University
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SCOPUS
Bibliographic Citation
Cell Stem Cell. Vol.20, No.6 (2017), 785-800.e8
Suggested Citation
Rebekka K. Schneider, Ann Mullally, Aurelien Dugourd, Fabian Peisker, Remco Hoogenboezem, Paulina M.H. Van Strien, Eric M. Bindels, Dirk Heckl, Guntram Büsche, David Fleck, Gerhard Müller-Newen, Janewit Wongboonsin, Monica Ventura Ferreira, Victor G. Puelles, Julio Saez-Rodriguez, Benjamin L. Ebert, Benjamin D. Humphreys, Rafael Kramann Gli1<sup>+</sup> Mesenchymal Stromal Cells Are a Key Driver of Bone Marrow Fibrosis and an Important Cellular Therapeutic Target. Cell Stem Cell. Vol.20, No.6 (2017), 785-800.e8. doi:10.1016/j.stem.2017.03.008 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/41898
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Title
Gli1<sup>+</sup> Mesenchymal Stromal Cells Are a Key Driver of Bone Marrow Fibrosis and an Important Cellular Therapeutic Target
Author(s)
Rebekka K. Schneider
Ann Mullally
Aurelien Dugourd
Fabian Peisker
Remco Hoogenboezem
Paulina M.H. Van Strien
Eric M. Bindels
Dirk Heckl
Guntram Büsche
David Fleck
Gerhard Müller-Newen
Janewit Wongboonsin
Monica Ventura Ferreira
Victor G. Puelles
Julio Saez-Rodriguez
Benjamin L. Ebert
Benjamin D. Humphreys
Rafael Kramann
Ann Mullally
Aurelien Dugourd
Fabian Peisker
Remco Hoogenboezem
Paulina M.H. Van Strien
Eric M. Bindels
Dirk Heckl
Guntram Büsche
David Fleck
Gerhard Müller-Newen
Janewit Wongboonsin
Monica Ventura Ferreira
Victor G. Puelles
Julio Saez-Rodriguez
Benjamin L. Ebert
Benjamin D. Humphreys
Rafael Kramann
Other Contributor(s)
Erasmus MC Cancer Institute
Rheinisch-Westfälische Technische Hochschule Aachen
Brigham and Women's Hospital
Medizinische Fakultät und Universitäts Klinikum Aachen
Medizinische Hochschule Hannover (MHH)
University of Minnesota Twin Cities
Mahidol University
Washington University School of Medicine in St. Louis
Rheinisch-Westfälische Technische Hochschule Aachen
Brigham and Women's Hospital
Medizinische Fakultät und Universitäts Klinikum Aachen
Medizinische Hochschule Hannover (MHH)
University of Minnesota Twin Cities
Mahidol University
Washington University School of Medicine in St. Louis
Abstract
© 2017 Elsevier Inc. 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. Schneider and colleagues show that Gli1+ bone marrow mesenchymal stromal cells are an important source of fibrotic cells during bone marrow fibrosis and that targeting of Gli proteins with GANT61 holds promise for amelioration of this disease.