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Developmental origins of fibroblasts determine their scarring potential in wound healing

ABSTRACT: Fibroblasts are the primary cells responsible for depositing extracellular matrix proteins during wound repair and fibrosis. Progress towards the development of treatments aimed at reducing scars has been hampered by our limited understanding of specific fibroblast populations responsible for fibrotic versus regenerative healing. Using a four-site wounding model in mice, we observed that neural crest-derived facial wounds heal with less scarring than cephalic mesoderm-derived scalp wounds, lateral plate mesoderm-derived ventral wounds, and paraxial mesoderm-derived dorsal wounds. Single-cell RNA sequencing identified increased expression of Robo2 and downstream Eid1 in neural-crest derived facial fibroblasts compared to fibroblasts from other sites. Subsequent fibroblast transplantation experiments showed that Robo2 and Eid1 are required for facial fibroblasts’ intrinsic reduced fibrotic potential. This is maintained by the EID1-mediated inhibition of EP300 histone acetyltransferase, leading to a more transcriptionally silent chromatin landscape, including around extracellular matrix genes. Mimicking EID1’s endogenous activity, both small-molecule and transgenic repression of EP300 in dorsal wounds promoted facial-like healing with reduced scarring. Overall, these data highlight the importance of the ROBO2-EID1-EP300 signaling axis in facial wound healing, and demonstrate our ability to modulate the embryologically determined fibrogenic potential of fibroblasts as a therapeutic approach to minimize scar formation.

ORGANISM(S): Mus musculus

PROVIDER: GSE248850 | GEO | 2026/02/12

REPOSITORIES: GEO

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Project description:Bacterial infections of wounds are associated with poor healing and worse scarring. We sought to identify transcriptomic patterns associated with impaired healing of wounds infected with Klebsiella pneumoniae (K.p.) or Pseudomonas aeruginosa (P.a.) using a rabbit ear wound model. Wounds created on post-operative day (POD) 0 were infected on POD3, within the inflammatory phase of healing. On POD4 the infected wounds were harvested for microarray/transcriptome analysis. Other wounds with 24-hour infections were treated with topical antibiotic to promote biofilm formation and harvested on POD6 or POD12. On POD4 before antibiotic treatment, both wounds contained elevated transcripts that enriched predominantly into inflammation/infection-response pathways and functions characteristic of infiltrating leukocytes. But there were 5-fold more elevated transcripts in P.a.- than K.p.-infected wounds. Additionally, unique to P.a.-infected wounds, was a minor network of inflammation/infection-response molecules with predicted upstream regulation predominated by type I interferons. Also on POD4, Dnr-transcripts of both wounds were enriched into stress-response pathways such as EIF2 signaling. But there were 8-fold more Dnr-transcripts in P.a.- than K.p.-infected wounds, and many more of them enriched in the function, cell death, suggesting that resident dermal cells of P.a.-infected wounds failed to survive a more destructive P.a. infection. On POD6, following two days of antibiotic treatment, the biofilm-colonized wounds expressed magnitudes fewer inflammation and stress-response transcripts. However, a single regulatory network of P.a.-infected wounds was found to consist of Upr-transcripts enriching immune/infection-response functions predicted to be regulated by type I interferons, which was similar to the network unique to P.a.-infected wounds on POD4. On POD12, genes expressed by K.p.-infected wounds suggesting healing, while for P.a.-infected wounds they suggested stalled healing. The similarities and differences between the wound responses to these infections further define the molecular foundations of healing impaired by infections. Rabbit ear Wounds created on post-operative day (POD) 0 were infected with Klebsiella pneumoniae (K.p.) or Pseudomonas aeruginosa (P.a.) on POD3 and harvested on POD4 for RNA extraction. Other wounds with 24-hour infections were treated with topical antibiotic to promote biofilm formation and harvested on POD6 or POD12.

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Developmental origins of fibroblasts determine their scarring potential in wound healing

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