Almet Axel A, Liu Yingzi, Nie Qing, Plikus Maksim V
Department of Mathematics, University of California, Irvine, Irvine, California, USA; NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, California, USA.
Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, California, USA.
J Invest Dermatol. 2025 Mar;145(3):645-659.e25. doi: 10.1016/j.jid.2024.06.1281. Epub 2024 Jul 15.
Wound healing is a dynamic process over temporal and spatial scales. Key to repair outcomes are fibroblasts; yet, how they modulate healing across time and in different wound regions remains incompletely understood. By integrating single-cell RNA-sequencing datasets of mouse skin and wounds, we infer that fibroblasts are the most transcriptionally dynamic skin-resident cells, evolving during postnatal skin maturation and rapidly after injury toward distinct late scar states. We show that transcriptional dynamics in fibroblasts are largely driven by genes encoding extracellular matrix and signaling factors. Lineage trajectory inference and spatial gene mapping reveal that Prg4-expressing fibroblasts transiently emerge along early wound edges. Within days, they become replaced by long-lasting and likely noninterconverting fibroblast populations, including Col25a1-expressing and Pamr1-expressing fibroblasts that occupy subepidermal and deep scar regions, respectively, where they engage in reciprocal signaling with immune cells. Signaling inference shows that fibroblast-immune crosstalk repeatedly uses some signaling pathways across wound healing time, whereas use of other signaling pathways is time and space limited. Collectively, we uncovered high transcriptional plasticity by wound fibroblasts, with early states transiently forming distinct microniches along wound edges and in the fascia, followed by stable states that stratify scar tissue into molecularly dissimilar upper and lower layers.
伤口愈合是一个跨越时间和空间尺度的动态过程。修复结果的关键在于成纤维细胞；然而，它们如何在不同时间和不同伤口区域调节愈合仍未完全明确。通过整合小鼠皮肤和伤口的单细胞RNA测序数据集，我们推断成纤维细胞是转录上最具动态变化的皮肤驻留细胞，在出生后皮肤成熟过程中不断演变，并在受伤后迅速朝着不同的晚期瘢痕状态发展。我们发现，成纤维细胞的转录动态变化在很大程度上由编码细胞外基质和信号因子的基因驱动。谱系轨迹推断和空间基因图谱显示，表达Prg4的成纤维细胞在伤口早期边缘短暂出现。数天内，它们被持久且可能无法相互转化的成纤维细胞群体取代，包括分别占据表皮下和深部瘢痕区域的表达Col25a1和成纤维细胞和表达Pamr1的成纤维细胞，它们在这些区域与免疫细胞进行相互信号传导。信号推断表明，成纤维细胞与免疫细胞的相互作用在伤口愈合过程中反复使用一些信号通路，而其他信号通路的使用则受时间和空间限制。总体而言，我们发现伤口成纤维细胞具有高度的转录可塑性，早期状态在伤口边缘和筋膜中短暂形成不同的微环境，随后是稳定状态，将瘢痕组织分层为分子组成不同的上层和下层。
