Mechanical checkpoint regulates monocyte differentiation in fibrotic niches.
Kyle H ViningAnna E MarnethKwasi Adu-BerchieJoshua M GrolmanChristina M TringidesYutong LiuWaihay J WongOlga PozdnyakovaMariano SevergniniAlexander StaffordGeorg N DudaF Stephen HodiAnn MullallyKai W WucherpfennigDavid J MooneyPublished in: Nature materials (2022)
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.
Keyphrases
- bone marrow
- dendritic cells
- endothelial cells
- extracellular matrix
- mesenchymal stem cells
- immune response
- regulatory t cells
- high glucose
- systemic sclerosis
- gene expression
- idiopathic pulmonary fibrosis
- multiple sclerosis
- stem cells
- transcription factor
- induced apoptosis
- dna damage
- induced pluripotent stem cells
- signaling pathway
- peripheral blood
- drug delivery
- acute myeloid leukemia
- mass spectrometry
- pi k akt
- hyaluronic acid