@article{876c606d4c0d4434a5be7c57bc7bab9c,
title = "Mechanical checkpoint regulates monocyte differentiation in fibrotic niches",
abstract = "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.",
author = "Vining, \{Kyle H.\} and Marneth, \{Anna E.\} and Kwasi Adu-Berchie and Grolman, \{Joshua M.\} and Tringides, \{Christina M.\} and Yutong Liu and Wong, \{Waihay J.\} and Olga Pozdnyakova and Mariano Severgnini and Alexander Stafford and Duda, \{Georg N.\} and Hodi, \{F. Stephen\} and Ann Mullally and Wucherpfennig, \{Kai W.\} and Mooney, \{David J.\}",
note = "Funding Information: At the Wyss Institute, we thank T. Ferrante for assistance with imaging, and group members D. Zhang and A. Gonzalez-Pujana for their assistance and feedback on this work. At Massachusetts General Hospital, we thank D. Lagares for his feedback and editing. At the Massachusetts Institute of Technology, the authors thank T. Gierahn and the BioMicroCenter for assistance with bulk RNA-sequencing. At Dana-Farber Cancer Research Institute, we thank C. Laurore for technical assistance. Part of this work was performed at the Bauer Core Facility at Harvard University. We thank S. Reinke and his Cell Harvest Unit of the Berlin Institute of Health Center for Regenerative Therapies and the Charit{\'e} for supply of the human fracture haematoma samples. We acknowledge Sysmex America, M. Sola-Visner and her laboratory members E. Nolton and P. Davenport (Boston Children{\textquoteright}s Hospital) for kindly sharing Sysmex equipment for complete blood counts. Research reported in this manuscript was supported by the National Cancer Institute of the National Institutes of Health under award number U01CA214369 (D.J.M.), the National Institute of Dental \& Craniofacial Research of the National Institutes of Health under award numbers K08DE025292 and K99DE030084 (K.H.V.), the Federal Drug Administration R01FD006589 (D.J.M.), and the Harvard University Materials Research Science and Engineering Center (grant DMR 1420570). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Parts of the work were supported by the Einstein foundation and the German Research Foundation in the context of the DFG FOR 2165 grant and CRC 1444 grants (G.N.D.). A.E.M. was supported by a long-term fellowship from the European Molecular Biology Organization (EMBO, ALTF 268-2017) and Horizon award from the US Department of Defense (W81XWH-20-1-0904). A.M. is a Scholar of the Leukaemia and Lymphoma Society (LLS). O.P. was supported by a Brigham and Women{\textquoteright}s Hospital Faculty Career Development Award and by the Brigham Research Institute and the Center for Faculty Development and Diversity{\textquoteright}s Office for Research Careers Microgrant Program. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2022",
month = aug,
doi = "10.1038/s41563-022-01293-3",
language = "English",
volume = "21",
pages = "939--950",
journal = "Nature Materials",
issn = "1476-1122",
publisher = "Nature Research",
number = "8",
}