Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis.

Alarmins Animals Bone Marrow Humans Mesenchymal Stem Cells Mice Myeloproliferative Disorders Primary Myelofibrosis
DAMP alarmins biomarker bone marrow fibrosis drug target hematopoietic stem cells mesenchymal stromal cells microenvironment myeloproliferative neoplasms single cell RNA sequencing

Journal

Cell stem cell
ISSN: 1875-9777
Titre abrégé: Cell Stem Cell
Pays: United States
ID NLM: 101311472

Informations de publication

Date de publication:
01 04 2021
Historique:
received: 15 11 2019
revised: 18 08 2020
accepted: 09 11 2020
pubmed: 11 12 2020
medline: 20 5 2021
entrez: 10 12 2020
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.stem.2020.11.004 PMID: 33301706 PMC: PMC8024900
pubmed: 33301706
pii: S1934-5909(20)30542-7
doi: 10.1016/j.stem.2020.11.004
pmc: PMC8024900
pii:
doi:

Substances chimiques

Alarmins 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

637-652.e8

Informations de copyright

Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

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Auteurs

Nils B Leimkühler (NB)

Department of Hematology, Erasmus Medical Center, Rotterdam 3015GD, the Netherlands.

Hélène F E Gleitz (HFE)

Department of Hematology, Erasmus Medical Center, Rotterdam 3015GD, the Netherlands.

Li Ronghui (L)

Institute for Computational Genomics, Faculty of Medicine, RWTH Aachen University, Aachen 52074 Germany.

Inge A M Snoeren (IAM)

Department of Hematology, Erasmus Medical Center, Rotterdam 3015GD, the Netherlands.

Stijn N R Fuchs (SNR)

Department of Hematology, Erasmus Medical Center, Rotterdam 3015GD, the Netherlands.

James S Nagai (JS)

Institute for Computational Genomics, Faculty of Medicine, RWTH Aachen University, Aachen 52074 Germany.

Bella Banjanin (B)

Department of Hematology, Erasmus Medical Center, Rotterdam 3015GD, the Netherlands.

King H Lam (KH)

Department of Pathology, Erasmus Medical Center, Rotterdam 3015GD, the Netherlands.

Thomas Vogl (T)

Institute of Immunology, University of Münster, Münster 49148, Germany.

Christoph Kuppe (C)

Division of Nephrology and Clinical Immunology, Faculty of Medicine, RWTH Aachen University, Aachen 52074, Germany.

Ursula S A Stalmann (USA)

Department of Hematology, Erasmus Medical Center, Rotterdam 3015GD, the Netherlands.

Guntram Büsche (G)

Institute of Pathology, Hannover Medical School, Hannover 30625, Germany.

Hans Kreipe (H)

Institute of Pathology, Hannover Medical School, Hannover 30625, Germany.

Ines Gütgemann (I)

Institute of Pathology, University of Bonn, Bonn 53127, Germany.

Philippe Krebs (P)

Institute of Pathology, University of Bern, Bern 3012, Switzerland.

Yara Banz (Y)

Institute of Pathology, University of Bern, Bern 3012, Switzerland.

Peter Boor (P)

Institute of Pathology, Faculty of Medicine, RWTH Aachen University, Aachen 52074, Germany.

Evelyn Wing-Yin Tai (EW)

Institute of Pathology, Faculty of Medicine, RWTH Aachen University, Aachen 52074, Germany.

Tim H Brümmendorf (TH)

Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen 52074, Germany.

Steffen Koschmieder (S)

Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen 52074, Germany.

Martina Crysandt (M)

Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen 52074, Germany.

Eric Bindels (E)

Department of Hematology, Erasmus Medical Center, Rotterdam 3015GD, the Netherlands.

Rafael Kramann (R)

Division of Nephrology and Clinical Immunology, Faculty of Medicine, RWTH Aachen University, Aachen 52074, Germany; Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen 52074, Germany.

Ivan G Costa (IG)

Institute for Computational Genomics, Faculty of Medicine, RWTH Aachen University, Aachen 52074 Germany.

Rebekka K Schneider (RK)

Department of Hematology, Erasmus Medical Center, Rotterdam 3015GD, the Netherlands; Department of Cell Biology, Institute for Biomedical Engineering, Faculty of Medicine, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany; Oncode Institute, Erasmus Medical Center, Rotterdam 3015GD, the Netherlands. Electronic address: reschneider@ukaachen.de.

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Classifications MeSH

questionsmedicales.fr › Facteurs biologiques › Médiateurs de l'inflammation › Alarmines › Heterogeneous bone-marrow stromal progenitors...
questionsmedicales.fr › Eucaryotes › Animaux › Heterogeneous bone-marrow stromal progenitors...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Moelle osseuse › Heterogeneous bone-marrow stromal progenitors...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Heterogeneous bone-marrow stromal progenitors...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches multipotentes › Cellules souches mésenchymateuses › Heterogeneous bone-marrow stromal progenitors...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Heterogeneous bone-marrow stromal progenitors...
questionsmedicales.fr › Hémopathies et maladies lymphatiques › Hémopathies › Maladies de la moelle osseuse › Syndromes myéloprolifératifs › Heterogeneous bone-marrow stromal progenitors...
questionsmedicales.fr › Hémopathies et maladies lymphatiques › Hémopathies › Maladies de la moelle osseuse › Syndromes myéloprolifératifs › Myélofibrose primitive › Heterogeneous bone-marrow stromal progenitors...