The identification of fibrosis-driving myofibroblast precursors reveals new therapeutic avenues in myelofibrosis

Abstract

Myofibroblasts are fibrosis-driving cells and are well characterized in solid organ fibrosis, but their role and cellular origin in bone marrow fibrosis remains obscure. Recent work has demonstrated that Gli1 and LepR mesenchymal stromal cells (MSCs) are progenitors of fibrosis-causing myofibroblasts in the bone marrow. Genetic ablation of Gli1 MSCs or pharmacologic targeting of hedgehog (Hh)-Gli signaling ameliorated fibrosis in mouse models of myelofibrosis (MF). Moreover, pharmacologic or genetic intervention in platelet-derived growth factor receptor α () signaling in stromal cells suppressed their expansion and ameliorated MF. Improved understanding of cellular and molecular mechanisms in the hematopoietic stem cell niche that govern the transition of MSCs to myofibroblasts and myofibroblast expansion in MF has led to new paradigms in the pathogenesis and treatment of MF. Here, we highlight the central role of malignant hematopoietic clone-derived megakaryocytes in reprogramming the hematopoietic stem cell niche in MF with potential detrimental consequences for hematopoietic reconstitution after allogenic stem cell transplantation, so far the only therapeutic approach in MF considered to be curative. We and others have reported that targeting Hh-Gli signaling is a therapeutic strategy in solid organ fibrosis. Data indicate that targeting Gli proteins directly inhibits Gli1 cell proliferation and myofibroblast differentiation, which results in reduced fibrosis severity and improved organ function. Although canonical Hh inhibition (eg, smoothened [Smo] inhibition) failed to improve pulmonary fibrosis, kidney fibrosis, or MF, the direct inhibition of Gli proteins ameliorated fibrosis. Therefore, targeting Gli proteins directly might be an interesting and novel therapeutic approach in MF.

Murine Bone Marrow Niches from Hematopoietic Stem Cells to B Cells

“…More recently, and thanks to the use of reporter mice, the progress made in understanding BM organization and BM stromal cell heterogeneity has been tremendous. The influence of the BM microenvironment on pathologies affecting hematopoietic progenitors has benefited from the important advances in normal HSC niche characterization [128,129]. Resistance and relapse in the case of B cell acute lymphoblastic leukemia, the pathological equivalent of differentiating B cells, also concerns a great proportion of patients, most particularly adults.…”

Mechanosensing by Gli1+ cells contributes to the orthodontic force‐induced bone remodelling

“…The double transgenic mice received 100 μg/g of body weight tamoxifen in corn oil for 3 consecutive days via intraperitoneal injection. To inhibit the expression of Gli1 protein, 40 mg/kg GANT61 (Med Chem Express, USA, HY‐13901) dissolved in ethanol: corn oil (1:4) was administered in mice every other day as recommended 16 . The vehicle was administrated to the control group.…”

Remodeling the Bone Marrow Microenvironment – A Proposal for Targeting Pro-inflammatory Contributors in MPN

“…Therapeutically targeting the BM stroma has gained more attention in the treatment of MF ( 59 , 98 ). As highlighted before, Gli1 + MSC were shown to be an important driver of MF in mouse models highlighting them as a potential therapeutic target.…”