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Space-time Mapping Identifies Concerted Multicellular Patterns and Gene Programs in Healing Wounds and their Conservation in Cancers.

ABSTRACT: Tissue repair responses in metazoans are highly coordinated by different cell types over space and time. However, comprehensive single-cell based characterization covering this coordination is lacking. Here, we captured transcriptional states of single cells over space and time during skin wound closure, revealing choreographed gene expression profiles. We identified shared and prominent space-time patterns of cellular and gene expression enrichment: which we call multicellular ‘movements’ and which spanned multiple cell types. We validated some of the discovered space-time movements using large volume imaging of cleared wounds and demonstrated the value of this analysis to predict gene products made by macrophages or fibroblasts, which activated gene programs in the opposite cell type. Finally, using two different tumor models, we tested the hypothesis that tumors are like ‘wounds that never heal’ finding conserved wound healing movements in the tumor space, wherein some movements were preferentially used in one tumor versus another.

ORGANISM(S): Mus musculus

PROVIDER: GSE204777 | GEO | 2022/05/28

REPOSITORIES: GEO

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Project description:While considerable progress has been made towards understanding the complex processes and pathways that regulate human wound healing, regenerative medicine has been unable to develop therapies that coax the natural wound environment to heal scar-free. The inability to induce perfect skin regeneration stems partly from our limited understanding of how scar-free healing occurs in a natural setting. Here we have investigated the wound repair process in adult axolotls and demonstrate that they are capable of perfectly repairing full thickness excisional wounds made on the flank. In the context of mammalian wound repair, our findings reveal a substantial reduction in hemostasis, reduced neutrophil infiltration and a relatively long delay in production of new extracellular matrix (ECM) during scar-free healing. Additionally, we test the hypothesis that metamorphosis leads to scarring and instead show that terrestrial axolotls also heal scar-free, albeit at a slower rate. Analysis of newly forming dermal ECM suggests that low levels of fibronectin and high levels of tenascin-C promote regeneration in lieu of scarring. Lastly, a genetic analysis during wound healing comparing epidermis between aquatic and terrestrial axolotls suggests that matrix metalloproteinases may regulate the fibrotic response. Our findings outline a blueprint to understand the cellular and molecular mechanisms coordinating scar-free healing that will be useful towards elucidating new regenerative therapies targeting fibrosis and wound repair. We used microarray analysis to determine the gene expression changes that take place during scar free wound healing in aquatic and terrestrial axolotl salamanders. Epidermal tissue was harvested using a 4mm biopsy punch. Two wounds were made along the flank and posterior to the forelimbs. Harvested epidermis was pooled for each animal. Four biological replicates were collected from uninjured epidermis (D0) and at 1, 3, and 7 days post injury.

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Space-time Mapping Identifies Concerted Multicellular Patterns and Gene Programs in Healing Wounds and their Conservation in Cancers.

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