Gli1 + Mesenchymal Stromal Cells Are a Key Driver of Bone Marrow Fibrosis and an Important Cellular Therapeutic Target
| Autor: | Benjamin L. Ebert, Victor G. Puelles, Gerhard Müller-Newen, David Fleck, Eric M.J. Bindels, Janewit Wongboonsin, Remco Hoogenboezem, Paulina M. H. van Strien, Dirk Heckl, Mónica S. Ventura Ferreira, Aurelien Dugourd, Benjamin D. Humphreys, Fabian Peisker, Rebekka K. Schneider, Julio Saez-Rodriguez, Rafael Kramann, Guntram Büsche, Ann Mullally |
|---|---|
| Přispěvatelé: | Hematology |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Pyridines Cell Bone marrow fibrosis Mice Transgenic Zinc Finger Protein GLI1 Article Mice 03 medical and health sciences 0302 clinical medicine GLI1 Fibrosis Genetics medicine Animals Humans Myofibroblasts Myelofibrosis Cell Proliferation biology integumentary system Mesenchymal stem cell Bone marrow failure Cell Differentiation Mesenchymal Stem Cells Cell Biology medicine.disease Phenotype 3. Good health Pyrimidines 030104 developmental biology medicine.anatomical_structure Primary Myelofibrosis 030220 oncology & carcinogenesis Immunology biology.protein Cancer research Molecular Medicine Bone marrow Stem cell Myofibroblast |
| Zdroj: | Cell Stem Cell Cell Stem Cell, 20(6), 785-800.e8. Cell Press |
| ISSN: | 1934-5909 |
| DOI: | 10.1016/j.stem.2017.03.008 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|