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异质性骨髓基质祖细胞通过可用药理性警报素轴驱动骨髓纤维化。

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

机构信息

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

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

出版信息

Cell Stem Cell. 2021 Apr 1;28(4):637-652.e8. doi: 10.1016/j.stem.2020.11.004. Epub 2020 Dec 9.

DOI:10.1016/j.stem.2020.11.004
PMID:33301706
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8024900/
Abstract

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.

摘要

骨髓微环境中单个细胞成分对骨髓纤维化（MF）的功能贡献在骨髓增生性肿瘤（MPN）患者中尚未完全阐明。我们旨在通过对小鼠模型和患者样本进行单细胞水平的研究，生成 MPN/MF 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 以阶段依赖性的方式被重新编程，失去其祖细胞状态并在纤维化前阶段开始分化，并在纤维化阶段获得促纤维化和炎症表型。警报素复合物 S100A8/S100A9 在 MSC 中的表达标志着小鼠模型和患者基质和血浆中向纤维化阶段的疾病进展。Tasquinimod 是一种抑制 S100A8/S100A9 信号的小分子，可显著改善 JAK2V617F 突变型小鼠模型的 MPN 表型和纤维化，这表明 S100A8/S100A9 是 MPN 中一个有吸引力的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2fcb/8024900/0d2a9f2d1984/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2fcb/8024900/c1833c5fb9bb/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2fcb/8024900/384d44a3a1ad/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2fcb/8024900/3c44dfc033eb/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2fcb/8024900/153a2f105a83/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2fcb/8024900/a7425542c724/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2fcb/8024900/b100ffb64caa/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2fcb/8024900/25fbd675f46a/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2fcb/8024900/0d2a9f2d1984/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2fcb/8024900/c1833c5fb9bb/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2fcb/8024900/384d44a3a1ad/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2fcb/8024900/3c44dfc033eb/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2fcb/8024900/153a2f105a83/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2fcb/8024900/a7425542c724/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2fcb/8024900/b100ffb64caa/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2fcb/8024900/25fbd675f46a/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2fcb/8024900/0d2a9f2d1984/gr7.jpg

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