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Cell Stem Cell. 2017 Jun 1;20(6):785-800.e8. doi: 10.1016/j.stem.2017.03.008. Epub 2017 Apr 27.

Gli1+ Mesenchymal Stromal Cells Are a Key Driver of Bone Marrow Fibrosis and an Important Cellular Therapeutic Target.

Author information

1
Department of Hematology, Erasmus MC Cancer Institute, 3015CN Rotterdam, the Netherlands; Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, RWTH Aachen University, 52074 Aachen, Germany. Electronic address: r.k.schneider@erasmusmc.nl.
2
Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
3
Joint Research Centre for Computational Biomedicine, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany.
4
Division of Nephrology and Clinical Immunology, RWTH Aachen University, 52074 Aachen, Germany.
5
Department of Hematology, Erasmus MC Cancer Institute, 3015CN Rotterdam, the Netherlands.
6
Division of Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany.
7
Institute of Pathology, Hannover Medical School, 30625 Hannover, Germany.
8
Department of Chemosensation, Institute of Biology II, RWTH Aachen University, 52074 Aachen, Germany.
9
Institute of Biochemistry and Molecular Biology, RWTH Aachen University, 52074 Aachen, Germany.
10
Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA; Department of Internal Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, 10700 Bangkok, Thailand.
11
Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, RWTH Aachen University, 52074 Aachen, Germany.
12
Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
13
Division of Nephrology and Clinical Immunology, RWTH Aachen University, 52074 Aachen, Germany. Electronic address: rkramann@gmx.net.

Abstract

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.

KEYWORDS:

Gli1; bone marrow fibrosis; mesenchymal stem cells; myelofibrosis; myeloproliferative neoplasms

PMID:
28457748
DOI:
10.1016/j.stem.2017.03.008
[Indexed for MEDLINE]
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