Cell stem cell · 2020
Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis.
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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-Yin, Brümmendorf Tim H, Koschmieder Steffen, Crysandt Martina, Bindels Eric, Kramann Rafael, Costa Ivan G, Schneider Rebekka K
Аннотация
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.