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

• Published in: Cell stem cell 2017-06, Vol.20 (6), p.785-800.e8
• Main Authors: Schneider, Rebekka K., Mullally, Ann, Dugourd, Aurelien, Peisker, Fabian, Hoogenboezem, Remco, Van Strien, Paulina M.H., Bindels, Eric M., Heckl, Dirk, Büsche, Guntram, Fleck, David, Müller-Newen, Gerhard, Wongboonsin, Janewit, Ventura Ferreira, Monica, Puelles, Victor G., Saez-Rodriguez, Julio, Ebert, Benjamin L., Humphreys, Benjamin D., Kramann, Rafael
• Format: Article
• Language: English
• Subjects: Animals; bone marrow fibrosis; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cell Proliferation - drug effects; Gli1; Humans; mesenchymal stem cells; Mesenchymal Stem Cells - metabolism; Mesenchymal Stem Cells - pathology; Mice; Mice, Transgenic; myelofibrosis; myeloproliferative neoplasms; 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
• ISSN: 1934-5909; 1875-9777; 1875-9777
• DOI: 10.1016/j.stem.2017.03.008

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. [Display omitted] •Bone marrow Gli1+ mesenchymal stromal cells (MSCs) differentiate into myofibroblasts•Targeting Gli1+ cells with GANT61 ameliorates bone marrow fibrosis (BMF)•Cxcl4 induces Gli1+ stromal cell migration and differentiation into myofibroblasts•Gli1+ MSCs also expand in human BMF and are sensitive to GANT61 inhibition 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.