@article {1662826,
	title = {Mechanical checkpoint regulates monocyte differentiation in fibrotic niches},
	journal = {Nat Mater},
	volume = {21},
	number = {8},
	year = {2022},
	month = {2022 Aug},
	pages = {939-950},
	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.},
	keywords = {Animals, Bone Marrow, Cell Differentiation, Fibrosis, Humans, Mice, Monocytes, Phosphatidylinositol 3-Kinases, Primary Myelofibrosis},
	issn = {1476-4660},
	doi = {10.1038/s41563-022-01293-3},
	author = {Vining, Kyle H and Marneth, Anna E and Adu-Berchie, Kwasi and Grolman, Joshua M and Tringides, Christina M and Liu, Yutong and Wong, Waihay J and Pozdnyakova, Olga and Severgnini, Mariano and Stafford, Alexander and Duda, Georg N and Hodi, F Stephen and Mullally, Ann and Wucherpfennig, Kai W and Mooney, David J}
}
