荷兰伊拉斯姆斯医学中心Rebekka K. Schneider研究组揭示异质性骨髓基质祖细胞如何驱动骨髓纤维化。相关论文于2020年12月9日在线发表于国际学术期刊《细胞—干细胞》。

据研究人员介绍，对于骨髓增生性肿瘤（MPN）患者，骨髓微环境的单个细胞成分对骨髓纤维化（MF）的功能贡献尚不完全清楚。

研究人员在在鼠模型和患者样本中的单细胞水平生成了MPN/MF中基质的综合图谱。这些分析揭示了作为促纤维化细胞的两个不同间充质基质细胞（MSC）亚群。以阶段依赖性方式对MSC进行功能性重编程，其会失去祖细胞状态并在纤维化前期开始分化，然后在纤维化期获得纤维化前和炎症性表型。在鼠模型以及患者基质和血浆中，alarmin复合物S100A8/S100A9在MSC中的表达标志着疾病向纤维化阶段发展。

Tasquinimod是一种抑制S100A8/S100A9信号的小分子，可显著改善JAK2V617F突变鼠模型的MPN表型和纤维化，从而突显出S100A8/S100A9是MPN的一个潜在治疗靶标。

附：英文原文

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

Author: Nils B. Leimkühler, Hélène F.E. Gleitz, Li Ronghui, Inge A.M. Snoeren, Stijn N.R. Fuchs, James S. Nagai, Bella Banjanin, King H. Lam, Thomas Vogl, Christoph Kuppe, Ursula S.A. 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

Issue&Volume: 2020-12-09

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.

DOI: 10.1016/j.stem.2020.11.004

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30542-7