Transcriptional changes in human palate and skin healing
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE209609 | GEO | 2022/12/29
REPOSITORIES: GEO
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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 skin’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.
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Project description:Studying the transcriptomic response of different epidermal stem cell populations to wounding has been difficult due to intermixing of wound healing and homeostastic cells from different stem cell pools in bulk-cell sequencing setups. Here, we circumvent those problems by using a single-cell sequencing approach. We randomly sequenced the traced progeny of either Lgr5 or Lgr6 stem cells isolated from wounded or unwounded skin 0 day (control), 1 d, 4 d, 7 d, 10 d or more than 1 month after wounding. We then identified Lgr5 or Lgr6 wound cells using a computational approach. Wound cells were defined by using a negative binominal Naïve Bayes classifier with 0-day control cells (unwounded mice) as reference. Wound cell populations were defined by clustering wound cells in t-SNE space using k-means clustering.
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