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Gli1Mesenchymal Stromal Cells Are a Key Driver of Bone Marrow Fibrosis and an Important Cellular Therapeutic Target.

Cell stem cell | 2017

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 Gli1mesenchymal stromal cells (MSCs) are recruited from the endosteal and perivascular niche to become fibrosis-driving myofibroblasts in the bone marrow. Genetic ablation of Gli1cells abolished BMF and rescued bone marrow failure. Pharmacological targeting of Gli proteins with GANT61 inhibited Gli1cell 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.

Pubmed ID: 28457748 RIS Download

Mesh terms: Animals | Cell Differentiation | Cell Proliferation | Humans | Mesenchymal Stem Cells | Mice | Mice, Transgenic | Myofibroblasts | Primary Myelofibrosis | Pyridines | Pyrimidines | Zinc Finger Protein GLI1

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BWA (tool)

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Software for aligning sequencing reads against large reference genome. Consists of three algorithms: one for sequence reads up to 100bp, and other two for longer sequences ranged from 70bp to 1Mbp.

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MultiQC (tool)

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Data aggregate that compiles results from bioinformatics analyses across multiple samples into a single report. It is written in Python.

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Stat5 (pY694) antibody (antibody)

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Human Nestin Phycoerythrin MAb (Clone 196908) antibody (antibody)

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Mouse Endoglin/CD105 MAb (Clone 209701) antibody (antibody)

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Anti-Mouse CD34 Alexa Fluor 700 100 ug antibody (antibody)

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Cell line HEK293T is aTransformed cell line with a species of origin Homo sapiens

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