Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis.
Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis.
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DOI：
10.1016/j.stem.2020.11.004
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发表时间：
2021-04-01
期刊：
影响因子：
23.9
通讯作者：
Schneider RK
中科院分区：
文献类型：
--
作者：
Leimkühler NB;Gleitz HFE;Ronghui L;Snoeren IAM;Fuchs SNR;Nagai JS;Banjanin B;Lam KH;Vogl T;Kuppe C;Stalmann USA;Büsche G;Kreipe H;Gütgemann I;Krebs P;Banz Y;Boor P;Tai EW;Brümmendorf TH;Koschmieder S;Crysandt M;Bindels E;Kramann R;Costa IG;Schneider RK
骨髓增生性肿瘤（MPN）患者骨髓微环境中单个细胞成分对骨髓纤维化（MF）的功能贡献尚不完全清楚。我们的目的是在鼠模型和患者样本中在单细胞水平上生成MPN/MF中基质的综合图谱。我们的分析揭示了两种不同的间充质基质细胞（MSC）亚群作为促纤维化细胞。MSC以阶段依赖性方式进行功能性重编程，在纤维化前丧失其祖细胞状态并开始分化，在纤维化阶段获得促纤维化和炎性表型。alarmin复合物S100 A8/S100 A9在MSC中的表达标志着在鼠模型中以及在患者基质和血浆中向纤维化阶段的疾病进展。他喹莫德是一种抑制S100 A8/S100 A9信号传导的小分子，在JAK 2 V617 F突变的鼠模型中显著改善了MPN表型和纤维化，突出了S100 A8/S100 A9是MPN中有吸引力的治疗靶点。间充质祖细胞是骨髓中的纤维化驱动细胞基质中的炎症表征预纤维化和TGF-β信号传导纤维化基质S100 A8/S100 A9标志着MPN患者的疾病进展他喹莫德，抑制S100 A8/S100 A9信号传导，改善MPN表型Leimkühler和同事证明间充质基质祖细胞是小鼠和患者中的纤维化驱动细胞，骨髓基质中的炎症先于TGF-β信号传导驱动的纤维化，并且alarmin异源复合物S100 A8/S100 A9有望作为MPN进展标志物和治疗靶点。
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. Mesenchymal progenitor cells are fibrosis-driving cells in the bone marrow Inflammation in the stroma characterizes pre-fibrosis and TGF-β signaling fibrosis Stromal S100A8/S100A9 marks disease progression in MPN patients Tasquinimod, inhibiting S100A8/S100A9 signaling, ameliorates the MPN phenotype Leimkühler and colleagues demonstrate that mesenchymal stromal progenitor cells are fibrosis-driving cells in mice and patients, that inflammation in the bone-marrow stroma precedes TGF-β signaling-driven fibrosis, and that the alarmin heterocomplex S100A8/S100A9 holds promise as MPN progression marker and therapeutic target.
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影响因子：
7.7
作者：
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