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

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, Maksim V. Plikus and Wendy F. Liu ()
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Sergei Butenko: 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
Michelle A. Digman: University of California Irvine
Qing Nie: University of California, Irvine
Philip O. Scumpia: University of California, Los Angeles
Maksim V. Plikus: University of California, Irvine
Wendy F. Liu: University of California Irvine

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50072-y

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