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

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

doi:10.1016/j.stem.2017.03.008

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

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

Authors

Rebekka K Schneider¹, Ann Mullally², Aurelien Dugourd³, Fabian Peisker⁴, Remco Hoogenboezem⁵, Paulina M H Van Strien⁵, Eric M Bindels⁵, Dirk Heckl⁶, Guntram Büsche⁷, David Fleck⁸, Gerhard Müller-Newen⁹, Janewit Wongboonsin¹⁰, Monica Ventura Ferreira¹¹, Victor G Puelles⁴, Julio Saez-Rodriguez³, Benjamin L Ebert², Benjamin D Humphreys¹², Rafael Kramann¹³

Affiliations

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.

MeSH terms

Animals
Cell Differentiation / drug effects*
Cell Differentiation / genetics
Cell Proliferation / drug effects*
Humans
Mesenchymal Stem Cells / metabolism*
Mesenchymal Stem Cells / pathology
Mice
Mice, Transgenic
Myofibroblasts / metabolism*
Myofibroblasts / pathology
Primary Myelofibrosis / drug therapy*
Primary Myelofibrosis / genetics
Primary Myelofibrosis / metabolism
Primary Myelofibrosis / pathology
Pyridines / pharmacology*
Pyrimidines / pharmacology*
Zinc Finger Protein GLI1 / antagonists & inhibitors*
Zinc Finger Protein GLI1 / genetics
Zinc Finger Protein GLI1 / metabolism

Substances

GANT 61
Gli1 protein, mouse
Pyridines
Pyrimidines
Zinc Finger Protein GLI1

Abstract

MeSH terms

Substances

Grants and funding