作者
Nils B. Leimkühler,Hélène F.E. Gleitz,Ronghui Li,Inge Snoeren,Stijn N.R. Fuchs,James S. Nagai,Bella Banjanin,King H. Lam,Thomas Vogl,Christoph Kuppe,Ursula Stalmann,Guntram Büsche,Hans Kreipe,Ines Gütgemann,Philippe Krebs,Yara Banz,Peter Boor,Evelyn Wing-Ying Tai,Tim H. Brümmendorf,Steffen Koschmieder,Martina Crysandt,Eric Bindels,Rafael Kramann,Ivan G. Costa,Rebekka K. Schneider
摘要
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.