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Cited by 69Cellular Mechanics and InteractionsAdvanced Materials and MechanicsTissue Engineering and Regenerative Medicine

Macrophages modulate stiffness-related foreign body responses through plasma membrane deformation

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Ni, Yueqi, Qi, Haoning, Zhang, Fanyu, Jiang, Shuting, Tang, Qinchao, Cai, Wenjin, Mo, Wenting, Miron, Richard J. +1 more·2023·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2213837120PMC PMC9934070
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Abstract

Implants are widely used in medical applications and yet macrophage-mediated foreign body reactions caused by implants severely impact their therapeutic effects. Although the extensive use of multiple surface modifications has been introduced to provide some mitigation of fibrosis, little is known about how macrophages recognize the stiffness of the implant and thus influence cell behaviors. Here, we demonstrated that macrophage stiffness sensing leads to differential inflammatory activation, resulting in different degrees of fibrosis. The potential mechanism for macrophage stiffness sensing in the early adhesion stages tends to involve cell membrane deformations on substrates with different stiffnesses. Combining theory and experiments, we show that macrophages exert traction stress on the substrate through adhesion and altered membrane curvature, leading to the uneven distribution of the curvature-sensing protein Baiap2, resulting in cytoskeleton remodeling and inflammation inhibition. This study introduces a physical model feedback mechanism for early cellular stiffness sensing based on cell membrane deformation, offering perspectives for future material design and targeted therapies.

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Research works printed but not linked: 42

  1. [1]E. A. Rankin, AJRR: Becoming a National US joint registry. Orthopedics 36, 175– 176 (2013). 23464934
  2. [2]P. Overtchouk, Advances in transcatheter mitral and tricuspid therapies. BMC Cardiovasc. Disord. 20, 1 (2020). 31910809 PMC6945613
  3. [3]K. Patel, K. Brandstetter, Solid implants in facial plastic surgery: Potential complications and how to prevent them. Facial Plast. Surg. 32, 520– 531 (2016). 27680524
  4. [4]Z. Li, Y. Cui, J. Zhong, Recent advances in nanogenerators-based flexible electronics for electromechanical biomonitoring. Biosens. Bioelectron. 186, 113290 (2021). 33965792
  5. [8]M. Kastellorizios, Foreign body reaction to subcutaneous implants. Adv. Exp. Med. Biol. 865, 93– 108 (2015). 26306445
  6. [9]B. N. Kharbikar, G. S. Chendke, T. A. Desai, Modulating the foreign body response of implants for diabetes treatment. Adv. Drug. Delivery Rev. 174, 87– 113 (2021). PMC8217111 33484736
  7. [10]J. Zdolsek, J. W. Eaton, L. Tang, Histamine release and fibrinogen adsorption mediate acute inflammatory responses to biomaterial implants in humans. J. Transl. Med. 5, 31 (2007). 17603911 PMC1929055
  8. [11]M. B. Gorbet, M. V. Sefton, Biomaterial-associated thrombosis: Roles of coagulation factors, complement, platelets and leukocytes. Biomaterials 25, 5681– 5703 (2004). 15147815
  9. [14]P. Thevenot, W. Hu, L. Tang, Surface chemistry influences implant biocompatibility. Curr. Top. Med. Chem. 8, 270– 280 (2008). 18393890 PMC3230929
  10. [16]W. J. Hadden, Stem cell migration and mechanotransduction on linear stiffness gradient hydrogels. Proc. Natl. Acad. Sci. U.S.A. 114, 5647– 5652 (2017). 28507138 PMC5465928
  11. [17]Z. Liu, Heterogeneous responses to mechanical force of prostate cancer cells inducing different metastasis patterns. Adv. Sci. (Weinh) 7, 1903583 (2020). 32775149 PMC7404165
  12. [18]A. K. Blakney, M. D. Swartzlander, S. J. Bryant, The effects of substrate stiffness on the in vitro activation of macrophages and in vivo host response to poly(ethylene glycol)-based hydrogels. J. Biomed. Mater. Res. A. 100, 1375– 1386 (2012). 22407522 PMC3339197
  13. [19]R. Sridharan, B. Cavanagh, A. R. Cameron, D. J. Kelly, F. J. O’Brien, Material stiffness influences the polarization state, function and migration mode of macrophages. Acta Biomater. 89, 47– 59 (2019). 30826478
  14. [21]O. Chaudhuri, J. Cooper-White, P. A. Janmey, D. J. Mooney, V. B. Shenoy, The impact of extracellular matrix viscoelasticity on cellular behavior. Nature 584, 535– 546 (2020). 32848221 PMC7676152
  15. [22]M. Maurer, J. Lammerding, The driving force: Nuclear mechanotransduction in cellular function, fate, and disease. Annu. Rev. Biomed. Eng. 21, 443– 468 (2019). 30916994 PMC6815102
  16. [23]Z. Sun, S. S. Guo, R. Fässler, Integrin-mediated mechanotransduction. J. Cell Biol. 215, 445– 456 (2016). 27872252 PMC5119943
  17. [24]F. Martino, A. R. Perestrelo, V. Vinarský, S. Pagliari, G. Forte, Cellular mechanotransduction: From tension to function. Front. Physiol. 9, 824 (2018). 30026699 PMC6041413
  18. [25]B. Cheng, Nanoscale integrin cluster dynamics controls cellular mechanosensing via FAKY397 phosphorylation. Sci. Adv. 6, eaax1909 (2020). 32181337 PMC7056303
  19. [26]J. Z. Kechagia, J. Ivaska, P. Roca-Cusachs, Integrins as biomechanical sensors of the microenvironment. Nat. Rev. Mol. Cell Biol. 20, 457– 473 (2019). 31182865
  20. [27]X. Zheng, Near-infrared-triggered dynamic surface topography for sequential modulation of macrophage phenotypes. ACS Appl. Mater. Interfaces 11, 43689– 43697 (2019). 31660718
  21. [28]H.-Y. Lou, Membrane curvature underlies actin reorganization in response to nanoscale surface topography. Proc. Natl. Acad. Sci. U.S.A. 116, 23143– 23151 (2019). 31591250 PMC6859365
  22. [30]E. Sitarska, A. Diz-Muñoz, Pay attention to membrane tension: Mechanobiology of the cell surface. Curr. Opin. Cell Biol. 66, 11– 18 (2020). 32416466 PMC7594640
  23. [31]F. Y. McWhorter, T. Wang, P. Nguyen, T. Chung, W. F. Liu, Modulation of macrophage phenotype by cell shape. Proc. Natl. Acad. Sci. U.S.A. 110, 17253– 17258 (2013). 24101477 PMC3808615
  24. [32]T. Nishimura, N. Morone, S. Suetsugu, Membrane re-modelling by BAR domain superfamily proteins via molecular and non-molecular factors. Biochem. Soc. Trans. 46, 379– 389 (2018). 29540508
  25. [33]Z. Jarin, Unusual organization of I-BAR proteins on tubular and vesicular membranes. Biophys. J. 117, 553– 562 (2019). 31349990 PMC6697384
  26. [34]A. Disanza, CDC42 switches IRSp53 from inhibition of actin growth to elongation by clustering of VASP. EMBO J. 32, 2735– 2750 (2013). 24076653 PMC3801440
  27. [35]D. J. Kast, Mechanism of IRSp53 inhibition and combinatorial activation by Cdc42 and downstream effectors. Nat. Struct. Mol. Biol. 21, 413– 422 (2014). 24584464 PMC4091835
  28. [36]J. Berthet, X. Varelas, Integrin-FAK-CDC42-PP1A signaling gnaws at YAP/TAZ activity to control incisor stem cells. Bioessays 39, 10.1002/bies.201700116 (2017). PMC5659350 28891248 · DOI
  29. [37]S. Kümper, C. J. Marshall, ROCK-driven actomyosin contractility induces tissue stiffness and tumor growth. Cancer Cell 19, 695– 697 (2011). 21665143
  30. [38]R. Sridharan, B. Cavanagh, A. R. Cameron, D. J. Kelly, F. J. O’Brien, Material stiffness influences the polarization state, function and migration mode of macrophages. Acta Biomater. 89, 47– 59 (2019). 30826478
  31. [39]A. Reversat, Cellular locomotion using environmental topography. Nature 582, 582– 585 (2020). 32581372
  32. [41]W. Bernhard, Lung surfactant: Function and composition in the context of development and respiratory physiology. Ann. Anat. 208, 146– 150 (2016). 27693601
  33. [42]L. Chen, Nanostructural surfaces with different elastic moduli regulate the immune response by stretching macrophages. Nano. Lett. 19, 3480– 3489 (2019). 31091110
  34. [43]N. Noskovicova, Suppression of the fibrotic encapsulation of silicone implants by inhibiting the mechanical activation of pro-fibrotic TGF-β. Nat. Biomed Eng. 5, 1437– 1456 (2021). 34031559
  35. [44]N. Q. Balaban, Force and focal adhesion assembly: A close relationship studied using elastic micropatterned substrates. Nat. Cell Biol. 3, 466– 472 (2001). 11331874
  36. [45]Y. Aratyn-Schaus, P. W. Oakes, J. Stricker, S. P. Winter, M. L. Gardel, Preparation of complaint matrices for quantifying cellular contraction. J. Vis. Exp. 2173 (2010). 21178972 PMC3159639
  37. [46]J. R. Tse, A. J. Engler, Preparation of hydrogel substrates with tunable mechanical properties. Curr. Protoc. Cell Biol. Chapter 10, Unit 10.16 (2010). 20521229
  38. [47]Z. Zhuang, Control of matrix stiffness using methacrylate-gelatin hydrogels for a macrophage-mediated inflammatory response. ACS Biomater Sci. Eng. 6, 3091– 3102 (2020). 33463297
  39. [49]A. Das, S. Adhikary, A. R. Chowdhury, A. Barui, Substrate-dependent control of the chiral orientation of mesenchymal stem cells: Image-based quantitative profiling. Biomed. Mater. 16, 034102 (2021). 33657017
  40. [50]Y. Xiong, A flexible, ultra-highly sensitive and stable capacitive pressure sensor with convex microarrays for motion and health monitoring. Nano. Energy 70, 104436 (2020).
  41. [51]L. Wang, L. Wang, L. Xu, W. Chen, Finite element modelling of single cell based on atomic force microscope indentation method. Comput. Math. Methods Med. 2019, 1– 10 (2019). PMC6942797 31933677
  42. [52]S. Barreto, C. H. Clausen, C. M. Perrault, D. A. Fletcher, D. Lacroix, A multi-structural single cell model of force-induced interactions of cytoskeletal components. Biomaterials 34, 6119– 6126 (2013). 23702149 PMC5513724

Cited by

Sorted by citations

Authors
Ni, Y., Qi, H., Zhang, F., Jiang, S., Tang, Q., Cai, W., Mo, W., Miron, R. J., & Zhang, Y.
Affiliations
Wuhan University (CN)
Corresponding author
Zhang, Yufeng
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2023-01-10
Volume
120
Issue
3
Pages
e2213837120-e2213837120
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2213837120
PMC
PMC9934070
OpenAlex
W4315436169
Cited by
69
References
7
Citations by year
2026: 29 · 2025: 16 · 2024: 18 · 2023: 6
FWCI
9.99
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • MOST | National Key Research and Development Program of China (2021YFC2400405)
  • National Natural Science Foundation of China (82025011)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Physical Sciences › Engineering › Mechanical Engineering › Advanced Materials and Mechanics
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
Keywords
macrophages, foreign body reaction, implant stiffness, cell membrane deformation, membrane curvature, BAIAP2, traction stress, cytoskeletal remodeling, inflammation, fibrosis, mechanotransduction, cell adhesion, substrate stiffness
MeSH terms
Cell Membrane, Fibrosis, Foreign-Body Reaction, Humans, Inflammation, Macrophages

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