4.8 Article

Mechanical checkpoint regulates monocyte differentiation in fibrotic niches

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NATURE MATERIALS
卷 21, 期 8, 页码 939-+

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NATURE PORTFOLIO
DOI: 10.1038/s41563-022-01293-3

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资金

  1. National Cancer Institute of the National Institutes of Health [U01CA214369]
  2. National Institute of Dental & Craniofacial Research of the National Institutes of Health [K08DE025292, K99DE030084]
  3. Federal Drug Administration [R01FD006589]
  4. Harvard University Materials Research Science and Engineering Center [DMR 1420570]
  5. Einstein foundation
  6. German Research Foundation [DFG FOR 2165, CRC 1444]
  7. European Molecular Biology Organization (EMBO) [ALTF 268-2017]
  8. US Department of Defense [W81XWH-20-1-0904]
  9. Brigham and Women's Hospital Faculty Career Development Award
  10. Brigham Research Institute
  11. Center for Faculty Development and Diversity's Office for Research Careers Microgrant Program

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Myelofibrosis causes pathological remodelling of the bone marrow, leading to increased stiffness and elasticity, thereby promoting the proliferation of proinflammatory monocytes and their differentiation into dendritic cells.
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-gamma. 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-gamma 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. Myelofibrosis causes a pathological remodelling of the bone marrow, which becomes stiffer and more elastic, thus promoting the proliferation of proinflammatory monocytes and their differentiation into dendritic cells.

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