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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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

IL-1β and TNFα participate in a wide range of immunoregulatory activities. The overproduction of these cytokines can result in inflammatory and autoimmune diseases. Monocytes are the main producers of both cytokines. In contrast, studies with highly purified polymorphonuclear leukocytes (PMN) showed their inability to synthesize IL-1β and TNFα. Mature monocytes and PMN are derived from the same precursors. However, the reason for the differential IL-1β and TNFα expression is not elucidated. Our study investigates the epigenetic mechanisms that may explain this apparent discrepancy. The expression and promoter accessibilities of IL-1β and TNFα genes of primary and in vitro differentiated monocytes and PMN and their common precursors were compared. The effects of histone deacetylase (HDAC)-inhibition by trichostatin A (TSA) on IL-1β and TNFα expression and their promoter structures were measured in promyeloid HL-60 cells. Cytokine expression was assessed by real-time PCR and ELISA. Chromatin structures were analyzed using chromatin accessibility by real-time PCR (CHART) assay. The proximal IL-1β promoter was remodeled into an open conformation during monopoiesis, but not granulopoiesis. Although stimulation-dependent, remodeling of the TNFα promoter was again only observed in monocytes. TSA activated IL-1β and TNFα expression and supported chromatin remodeling of their promoters in HL-60 cells. The ability to express IL-1β and TNFα is linked to a cell type specific promoter structure, which is established during monocytic but not granulocytic differentiation. The participation of acetylation in IL-1β and TNFα promoter activation shed new light on the regulation of IL-1β or TNFα expression. These data may have implications for understanding the progression from normal to disease conditions., (Copyright © 2012 Elsevier GmbH. All rights reserved.)