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Comparative proteomic analysis of skin wound healing responses to biomaterial treatments identifies key pathways which govern differential regenerative outcomes Comparative proteomic analysis of skin wound healing responses to biomaterial treatments identifies key pathways which govern differential regenerative outcomes

ABSTRACT: The wound healing cascade is characterized by the steady progression of distinct stages. Though biomaterials are used clinically to enhance wound closure rate and quality of healed tissue, their mechanisms of action are less understood. Here we use proteomic analysis to characterize changes in the wound healing response across three biomaterial treatments: a clinically used collagen hydrogel, and two synthetic biomaterials that are characterized by an increased regenerative response either through decreased fibrosis or through an activation of adaptive immunity. We identified close to 5,000 proteins shared across the biomaterial treatment groups, sampled at timepoints representing the inflammation, proliferation, and resolution phases of wound healing. The collagen hydrogel maintains an enrichment of immune-related pathways throughout the healing process. The fibrosis-suppressing material enriches gene ontology (GO) terms related to increased epidermis development pathways, collagen synthesis, and collagen fibril organization. In contrast, the adaptive immunity-activating biomaterial shows an early enrichment of GO terms related to broad immunity and inflammation. Later, this same material promotes keratinization, muscle and lipid oxidation GO pathways. Taken together, this work determines the key temporal pathways (immunity, keratinization, muscle system process, and ECM organization) mediated by three biomaterials, which result in varying healed tissue structure.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Skin, Fibroblast

DISEASE(S): Wounds And Injuries

SUBMITTER: Alejandra Suarez-Arnedo

LAB HEAD: David Muddiman

PROVIDER: PXD067152 | Pride | 2025-09-15

REPOSITORIES: Pride

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			Action	DRS
	20210909_HB_Woundhealing_10BL.raw	Raw
	20210909_HB_Woundhealing_10BR.raw	Raw
	20210909_HB_Woundhealing_10TL.raw	Raw
	20210909_HB_Woundhealing_10TR.raw	Raw
	20210909_HB_Woundhealing_1BL.raw	Raw

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Comparative proteomic analysis of skin wound healing responses to biomaterial treatments identifies key pathways which govern differential regenerative outcomes.

Suarez-Arnedo Alejandra A Caston Eleanor L P ELP Liu Yining Y Bai Hongxia H Muddiman David C DC Segura Tatiana T

Biomaterials 20250904

The wound healing cascade is characterized by the steady progression of distinct stages. Though biomaterials are used clinically to enhance wound closure rate and quality of healed tissue, their mechanisms of action are less understood. Here we use proteomic analysis to characterize changes in the wound healing response across three biomaterial treatments: a clinically used collagen hydrogel, and two synthetic biomaterials that are characterized by an increased regenerative response either throu ...[more]

PMID: 40939262

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Project description:Proteases control complex tissue responses by modulating inflammation, cell proliferation and migration, and matrix remodeling. All these processes are orchestrated in cutaneous wound healing to restore the skinâ€™s barrier function upon injury. Altered protease activity has been implicated in the pathogenesis of healing impairments, and proteases are important targets in diagnosis and therapy of this pathology. Global assessment of proteolysis at critical turning points after injury will define crucial events in acute healing that might be disturbed in healing disorders. As optimal biospecimens, wound exudates contain an ideal proteome to detect extracellular proteolytic events, are non-invasively accessible, and can be collected at multiple time points along the healing process from the same wound in the clinics. In this study, we applied multiplexed Terminal Amine Isotopic Labeling of Substrates (TAILS) to globally assess proteolysis in early phases of cutaneous wound healing. By quantitative analysis of proteins and protein N termini in wound fluids from a clinically relevant pig wound model, we identified more than 650 proteins and discerned major healing phases through distinctive abundance clustering of markers of inflammation, granulation tissue formation, and re-epithelialization. TAILS revealed a high degree of proteolysis at all time points after injury by detecting almost 1300 N-terminal peptides in ~450 proteins, most of which could not be assigned to known mature protein N termini. Quantitative positional proteomics mapped pivotal interdependent processing events in the blood coagulation cascade, detailed activating thrombin cleavages in vivo, and temporally discerned clotting and fibrinolysis during the healing process. Similarly, we found virtually all major cleavages in complement activation and inactivation and demonstrated time-dependent changes in the proteolytic potential of the wound milieu by detecting processing of complement C3 at distinct time points after wounding and by different proteases.

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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Comparative proteomic analysis of skin wound healing responses to biomaterial treatments identifies key pathways which govern differential regenerative outcomes.

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