Mechanical checkpoint regulates monocyte differentiation in fibrotic niches.
Mechanical checkpoint regulates monocyte differentiation in fibrotic niches.
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DOI：
10.1038/s41563-022-01293-3
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发表时间：
2022-08
期刊：
影响因子：
41.2
通讯作者：
中科院分区：
文献类型：
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骨髓纤维化是一种与单核细胞增多症相关的进行性骨髓恶性肿瘤，被认为会促进细胞外基质的病理性重塑。在这里，我们表明骨髓纤维化的机械特性，即骨髓的液体到固体特性（粘弹性），导致单核细胞的异常分化。与在粘弹性基质中培养的人单核细胞相反，在坚硬、有弹性的水凝胶中培养的人单核细胞表现出促炎性极化和向树突细胞的分化。这种机械诱导的细胞分化可通过抑制磷酸肌醇 3-激酶 PI3K-γ 的骨髓特异性亚型来阻断。我们进一步表明，患有骨髓纤维化的小鼠骨髓硬度显着增加，并揭示了骨髓纤维化分级与粘弹性之间的正相关性。体内使用 PI3K-γ 抑制剂治疗可降低患有骨髓纤维化的小鼠骨髓中单核细胞和树突状细胞群的频率。此外，粘弹性驱动的转录变化与其他人类纤维化疾病中骨髓细胞的转录谱一致。这些结果表明，纤维化骨髓生态位可以在物理上促进促炎微环境。
Myelofibrosis is a progressive bone marrow malignancy associated with monocytosis, and is believed to promote the pathological remodelling of the extracellular matrix. Here we show that the mechanical properties of myelofibrosis, namely the liquid-to-solid properties (viscoelasticity) of the bone marrow, contribute to aberrant differentiation of monocytes. Human monocytes cultured in stiff, elastic hydrogels show proinflammatory polarization and differentiation towards dendritic cells, as opposed to those cultured in a viscoelastic matrix. This mechanically induced cell differentiation is blocked by inhibiting a myeloid-specific isoform of phosphoinositide 3-kinase, PI3K-γ. We further show that murine bone marrow with myelofibrosis has a significantly increased stiffness and unveil a positive correlation between myelofibrosis grading and viscoelasticity. Treatment with a PI3K-γ inhibitor in vivo reduced frequencies of monocyte and dendritic cell populations in murine bone marrow with myelofibrosis. Moreover, transcriptional changes driven by viscoelasticity are consistent with transcriptional profiles of myeloid cells in other human fibrotic diseases. These results demonstrate that a fibrotic bone marrow niche can physically promote a proinflammatory microenvironment.
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影响因子：
--
作者：
Bartalucci N;Calabresi L;Balliu M;Martinelli S;Rossi MC;Villeval JL;Annunziato F;Guglielmelli P;Vannucchi AM
通讯作者：
Vannucchi AM
影响因子：
16.6
作者：
Chaudhuri O;Gu L;Darnell M;Klumpers D;Bencherif SA;Weaver JC;Huebsch N;Mooney DJ
通讯作者：
Mooney DJ
影响因子：
41.2
作者：
Chaudhuri O;Gu L;Klumpers D;Darnell M;Bencherif SA;Weaver JC;Huebsch N;Lee HP;Lippens E;Duda GN;Mooney DJ
通讯作者：
Mooney DJ
影响因子：
7.3
作者：
Grove, Lisa M.;Mohan, Maradumane L.;Olman, Mitchell A.
通讯作者：
Olman, Mitchell A.
DOI：
10.1016/j.clml.2013.07.011
发表时间：
2013-09-01
期刊：
Clinical lymphoma, myeloma & leukemia
影响因子：
--
作者：
Bartalucci, Niccolo;Guglielmelli, Paola;Vannucchi, Alessandro M
通讯作者：
Vannucchi, Alessandro M