Leimkühler, Nils B.; Gleitz, Hélène F.E.; Ronghui, Li; Snoeren, Inge A.M.; Fuchs, Stijn N.R.; Nagai, James S.; Banjanin, Bella; Lam, King H.; Vogl, Thomas; Kuppe, Christoph; Stalmann, Ursula S.A.; Büsche, Guntram; Kreipe, Hans; Gütgemann, Ines; Krebs, Philippe; Banz, Yara; Boor, Peter; Tai, Evelyn Wing-Ying; Brümmendorf, Tim H.; Koschmieder, Steffen; ... (2021). Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis. Cell stem cell, 28(4), 637-652.e8. Elsevier 10.1016/j.stem.2020.11.004
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Summary 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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Service Sector > Institute of Pathology > Cytopathology 04 Faculty of Medicine > Service Sector > Institute of Pathology 04 Faculty of Medicine > Service Sector > Institute of Pathology > Immunopathology |
UniBE Contributor: |
Krebs, Philippe, Banz Wälti, Yara Sarah |
Subjects: |
500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health |
ISSN: |
1934-5909 |
Publisher: |
Elsevier |
Language: |
English |
Submitter: |
Philippe Krebs |
Date Deposited: |
24 Dec 2020 12:02 |
Last Modified: |
02 Mar 2023 23:34 |
Publisher DOI: |
10.1016/j.stem.2020.11.004 |
PubMed ID: |
33301706 |
Uncontrolled Keywords: |
hematopoietic stem cells, mesenchymal stromal cells, bone marrow fibrosis, microenvironment, single cell RNA sequencing, myeloproliferative neoplasms, biomarker, alarmins, DAMP, drug target |
BORIS DOI: |
10.48350/149432 |
URI: |
https://boris.unibe.ch/id/eprint/149432 |
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