Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33301706.
- Also identified by DOI 10.1016/j.stem.2020.11.004 and PMC identifier 8024900.
- Licence recorded as CC BY-NC-ND.
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Abstract
Functional contributions of individual cellular components of the bone-marrow microenvironment to myelofibrosis (MF) in patients with myeloproliferative neoplasms (MPNs) are incompletely understood. We aimed to generate a comprehensive map of the stroma in MPNs/MFs on a single-cell level in murine models and patient samples. Our analysis revealed two distinct mesenchymal stromal cell (MSC) subsets as pro-fibrotic cells. MSCs were functionally reprogrammed in a stage-dependent manner with loss of their progenitor status and initiation of differentiation in the pre-fibrotic and acquisition of a pro-fibrotic and inflammatory phenotype in the fibrotic stage. The expression of the alarmin complex S100A8/S100A9 in MSC marked disease progression toward the fibrotic phase in murine models and in patient stroma and plasma. Tasquinimod, a small-molecule inhibiting S100A8/S100A9 signaling, significantly ameliorated the MPN phenotype and fibrosis in JAK2V617F-mutated murine models, highlighting that S100A8/S100A9 is an attractive therapeutic target in MPNs.
Medical subject headings
- Mesenchymal Stem Cells
- Myeloproliferative Disorders
- Primary Myelofibrosis