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

Authors
  • Kramann, Rafael1
  • Schneider, Rebekka K2, 3
  • 1 Division of Nephrology and Clinical Immunology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany. , (Germany)
  • 2 Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands; and. , (Netherlands)
  • 3 Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, RWTH Aachen University, Aachen, Germany. , (Germany)
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
May 10, 2018
Volume
131
Issue
19
Pages
2111–2119
Identifiers
DOI: 10.1182/blood-2018-02-834820
PMID: 29572380
Source
Medline
Language
English
License
Unknown

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 (Pdgfrα) signaling in Lepr+ 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. © 2018 by The American Society of Hematology.

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