Leimkühler, Nils B.Nils B.LeimkühlerGleitz, Hélène F.E.Hélène F.E.GleitzRonghui, LiLiRonghuiSnoeren, Inge A.M.Inge A.M.SnoerenFuchs, Stijn N.R.Stijn N.R.FuchsNagai, James S.James S.NagaiBanjanin, BellaBellaBanjaninLam, King H.King H.LamVogl, ThomasThomasVoglKuppe, ChristophChristophKuppeStalmann, Ursula S.A.Ursula S.A.StalmannBüsche, GuntramGuntramBüscheKreipe, HansHansKreipeGütgemann, InesInesGütgemannKrebs, PhilippePhilippeKrebs0000-0003-4918-6654Banz Wälti, Yara SarahYara SarahBanz Wälti0000-0003-4474-3132Boor, PeterPeterBoorTai, Evelyn Wing-YingEvelyn Wing-YingTaiBrümmendorf, Tim H.Tim H.BrümmendorfKoschmieder, SteffenSteffenKoschmiederCrysandt, MartinaMartinaCrysandtBindels, EricEricBindelsKramann, RafaelRafaelKramannCosta, Ivan G.Ivan G.CostaSchneider, Rebekka K.Rebekka K.Schneider2024-09-022024-09-022021-04-01https://boris-portal.unibe.ch/handle/20.500.12422/38656Summary 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.enhematopoietic stem cellsmesenchymal stromal cellsbone marrow fibrosismicroenvironmentsingle cell RNA sequencingmyeloproliferative neoplasmsbiomarkeralarminsDAMPdrug target500 - Science::570 - Life sciences; biology600 - Technology::610 - Medicine & healtharticle10.48350/1494323330170610.1016/j.stem.2020.11.004