Mechanical checkpoint regulates monocyte differentiation in fibrotic niches

Kyle H Vining; Anna E Marneth; Kwasi Adu-Berchie; Joshua M Grolman; Christina M Tringides; Yutong Liu; Waihay J Wong; Olga Pozdnyakova; Mariano Severgnini; Alexander Stafford; Georg N Duda; F Stephen Hodi; Ann Mullally; Kai W Wucherpfennig; David J Mooney

doi:10.1038/s41563-022-01293-3

Mechanical checkpoint regulates monocyte differentiation in fibrotic niches

Nat Mater. 2022 Aug;21(8):939-950. doi: 10.1038/s41563-022-01293-3. Epub 2022 Jul 11.

Authors

Kyle H Vining^#^{1

2

3

4

5}, Anna E Marneth^#⁶, Kwasi Adu-Berchie^{1

2}, Joshua M Grolman^{1

2

7}, Christina M Tringides^{8

9}, Yutong Liu^{1

2}, Waihay J Wong^{3

10}, Olga Pozdnyakova¹⁰, Mariano Severgnini¹¹, Alexander Stafford², Georg N Duda^{2

12

13}, F Stephen Hodi³, Ann Mullally^{3

6}, Kai W Wucherpfennig¹⁴, David J Mooney^{15

16}

Affiliations

¹ John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA.
² Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁴ Department of Preventative and Restorative Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Department of Materials Science and Engineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA.
⁶ Division of Hematology, Brigham and Women's Hospital, Boston, MA, USA.
⁷ Materials Science and Engineering, The Technion-Israel Institute of Technology, Haifa, Israel.
⁸ Harvard Program in Biophysics, Harvard University, Cambridge, MA, USA.
⁹ Harvard-MIT Division in Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁰ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹¹ Center for Immuno-Oncology Immune Assessment Laboratory at the Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
¹² Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration at Berlin Institute of Health and Charité - Universitätsmedizin, Berlin, Germany.
¹³ Berlin Institute of Health Center for Regenerative Therapies, Berlin Institute of Health and Charité - Universitätsmedizin, Berlin, Germany.
¹⁴ Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. kai_wucherpfennig@dfci.harvard.edu.
¹⁵ John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA. mooneyd@seas.harvard.edu.
¹⁶ Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA, USA. mooneyd@seas.harvard.edu.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Bone Marrow / pathology
Cell Differentiation
Fibrosis
Humans
Mice
Monocytes
Phosphatidylinositol 3-Kinases
Primary Myelofibrosis* / pathology

Abstract

Publication types

MeSH terms

Grants and funding