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.

中文翻译：

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Gli1 +间质基质细胞是骨髓纤维化的重要驱动力和重要的细胞治疗靶点

骨髓纤维化（BMF）在各种血液学和非血液学疾病中发展，是骨髓纤维化的主要病理特征。需要有效的针对细胞的治疗方法，但BMF的细胞起源仍然难以捉摸。在这里，我们显示了在BMF的两个鼠模型中使用遗传命运追踪显示，Gli1 +间质基质细胞（MSC）是从骨膜内和血管周围生境中募集而成为驱动纤维化的成肌纤维细胞在骨髓中产生的。Gli1 +细胞的遗传消融废除了BMF，挽救了骨髓衰竭。用GANT61靶向Gli蛋白的药理作用抑制了Gli1 +细胞的扩张和成纤维细胞的分化，并减轻了纤维化的严重程度。相同的途径在人BMF中也有活性，并且Bli中Gli1的表达与疾病的严重程度显着相关。此外，