Integrated Single-Cell Analysis Reveals Spatially and Temporally Dynamic Heterogeneity in Fibroblast States during Wound Healing
Year: 2024
Type: article
Abstract: 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.
Institution: University of California, Irvine
Language: English
Topic: Wound Healing and Treatments
Subfield: Rehabilitation
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,400
Funders: National Science Foundation, W. M. Keck Foundation, Simons Foundation, California Institute for Regenerative Medicine, National Sleep Foundation, Chan Zuckerberg Initiative, European Commission, LEO Fondet, National Institutes of Health, HORIZON EUROPE Framework Programme, National Institute of General Medical Sciences, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: G1454206734, Development and characterization of a pan-flavivirus vaccine candidate, G1553775739, G1822395139, G1956888977, G2318624699, CIRM Scholars Comprehensive Research Training Program, G3619989584, G3658124931, G3727843569, G3994878880, G4635388232, G5175704665, Leveraging immune-fibroblast interactions for biomaterial induced skin regeneration, G5398183627, G5613750303, G5781084482, G5805402537, G5991317503, G620175039, G623311797, G6791967163, NSF-Simons Center for Multiscale Cell Fate Research, G7958134206, G9000053800, G9000056806, G9000091357, G9000107770, G9000216479, G986754019
OpenAlex ID: W4400640360