Mechano-induced patterned domain formation by monocytes

Wenxuan Du; Jingyi Zhu; Yufei Wu; Hongyi Liu; Ashley L Kiemen; Zeqi Wan; Eban Andrew Hanna; Hui Zhang; Sean X Sun; Denis Wirtz

doi:10.1038/s41563-025-02397-2

Mechano-induced patterned domain formation by monocytes

Nat Mater. 2025 Nov 5. doi: 10.1038/s41563-025-02397-2. Online ahead of print.

Authors

Wenxuan Du^#^{1

2}, Jingyi Zhu^#^{2

3}, Yufei Wu^#^{2

4}, Hongyi Liu⁵, Ashley L Kiemen^{1

2

5}, Zeqi Wan^{2

6}, Eban Andrew Hanna^{1

2}, Hui Zhang^{5

7}, Sean X Sun^{8

9

10}, Denis Wirtz^{11

12

13

14

15}

Affiliations

¹ Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
² Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA.
³ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁴ Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁵ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Department of Biochemistry and Molecular Biology, Johns Hopkins University, Baltimore, MD, USA.
⁷ Johns Hopkins Physical Sciences-Oncology Center, Johns Hopkins University, Baltimore, MD, USA.
⁸ Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA. ssun@jhu.edu.
⁹ Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, USA. ssun@jhu.edu.
¹⁰ Johns Hopkins Physical Sciences-Oncology Center, Johns Hopkins University, Baltimore, MD, USA. ssun@jhu.edu.
¹¹ Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA. wirtz@jhu.edu.
¹² Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA. wirtz@jhu.edu.
¹³ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. wirtz@jhu.edu.
¹⁴ Johns Hopkins Physical Sciences-Oncology Center, Johns Hopkins University, Baltimore, MD, USA. wirtz@jhu.edu.
¹⁵ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. wirtz@jhu.edu.

^# Contributed equally.

PMID: 41193876
DOI: 10.1038/s41563-025-02397-2

Abstract

Matrix stiffness and the corresponding mechanosignalling play indispensable roles in cellular phenotypes and functions. How tissue stiffness influences the behaviour of monocytes, a major circulating leukocyte of the innate system, and how it may promote the emergence of collective cell behaviour is less understood. Here we show that human primary monocytes, uniquely among key immune cells, undergo a dynamic local phase separation to form highly regular, reversible, multicellular, multilayered domains on soft collagen-coated hydrogels of physiological stiffnesses. Local activation of the β2 integrin-ICAM-1 complex initiates intercellular adhesion, while global soluble inhibitory factors maintain the steady-state domain pattern over days. While inhibiting their phagocytic capability, domain formation promotes the survival of monocytes. A computational model incorporating the Cahn-Hilliard equation of phase separation with the Turing mechanism of local activation and global inhibition suggests that cell seeding density and chemotactic and random cell migration contribute to domain pattern formation, which is experimentally validated. This work reveals that cells can generate complex phases by exploiting their mechanosensing abilities and combined short-range interactions and long-range signals to enhance their survival.

Abstract

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