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Hydrogel crosslinking modulates macrophages, fibroblasts, and their communication, during wound healing

Author

Listed:
  • Sergei Butenko

    (University of California Irvine
    University of California, Irvine)

  • Raji R. Nagalla

    (University of California Irvine)

  • Christian F. Guerrero-Juarez

    (University of Illinois at Urbana-Champaign)

  • Francesco Palomba

    (University of California Irvine)

  • Li-Mor David

    (University of California Irvine)

  • Ronald Q. Nguyen

    (University of California Irvine)

  • Denise Gay

    (University of California, Irvine)

  • Axel A. Almet

    (University of California, Irvine
    University of California, Irvine)

  • Michelle A. Digman

    (University of California Irvine
    University of California)

  • Qing Nie

    (University of California, Irvine
    University of California, Irvine
    University of California Irvine)

  • Philip O. Scumpia

    (University of California, Los Angeles
    University of California, Los Angeles
    Veterans Administration Greater Los Angeles Healthcare System)

  • Maksim V. Plikus

    (University of California, Irvine
    University of California, Irvine
    University of California, Irvine)

  • Wendy F. Liu

    (University of California Irvine
    University of California Irvine
    University of California, Irvine
    University of California, Irvine)

Abstract

Biomaterial wound dressings, such as hydrogels, interact with host cells to regulate tissue repair. This study investigates how crosslinking of gelatin-based hydrogels influences immune and stromal cell behavior and wound healing in female mice. We observe that softer, lightly crosslinked hydrogels promote greater cellular infiltration and result in smaller scars compared to stiffer, heavily crosslinked hydrogels. Using single-cell RNA sequencing, we further show that heavily crosslinked hydrogels increase inflammation and lead to the formation of a distinct macrophage subpopulation exhibiting signs of oxidative activity and cell fusion. Conversely, lightly crosslinked hydrogels are more readily taken up by macrophages and integrated within the tissue. The physical properties differentially affect macrophage and fibroblast interactions, with heavily crosslinked hydrogels promoting pro-fibrotic fibroblast activity that drives macrophage fusion through RANKL signaling. These findings suggest that tuning the physical properties of hydrogels can guide cellular responses and improve healing, offering insights for designing better biomaterials for wound treatment.

Suggested Citation

  • Sergei Butenko & Raji R. Nagalla & Christian F. Guerrero-Juarez & Francesco Palomba & Li-Mor David & Ronald Q. Nguyen & Denise Gay & Axel A. Almet & Michelle A. Digman & Qing Nie & Philip O. Scumpia &, 2024. "Hydrogel crosslinking modulates macrophages, fibroblasts, and their communication, during wound healing," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50072-y
    DOI: 10.1038/s41467-024-50072-y
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    References listed on IDEAS

    as
    1. Hamza Atcha & Amit Jairaman & Jesse R. Holt & Vijaykumar S. Meli & Raji R. Nagalla & Praveen Krishna Veerasubramanian & Kyle T. Brumm & Huy E. Lim & Shivashankar Othy & Michael D. Cahalan & Medha M. P, 2021. "Mechanically activated ion channel Piezo1 modulates macrophage polarization and stiffness sensing," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    2. Suoqin Jin & Christian F. Guerrero-Juarez & Lihua Zhang & Ivan Chang & Raul Ramos & Chen-Hsiang Kuan & Peggy Myung & Maksim V. Plikus & Qing Nie, 2021. "Inference and analysis of cell-cell communication using CellChat," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
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