Hypertrophic scars (HS) are abnormal outcomes of wound healing, marked by excessive extracellular matrix (ECM) deposition and impaired scar remodeling. Fibroblasts are known to be central drivers of scar formation, but they are highly heterogeneous, meaning that different fibroblast subtypes may play different roles in collagen production, inflammation, vascular remodeling, and scar persistence. Current therapies remain limited partly because the key scar-driving cell states and upstream regulatory mechanisms are still not fully defined. Single-cell RNA sequencing (scRNA-seq) has opened a new window into scar biology, but identifying actionable regulators remains challenging. Based on these challenges, in-depth research is needed into fibroblast heterogeneity and transcriptional regulation in hypertrophic scar formation.
The study was conducted by researchers from the Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, and published (DOI: 10.1093/burnst/tkag027) in Burns & Trauma in 2026. The work used scRNA-seq, public dataset validation, transcription factor prediction, and functional experiments to explore how fibroblast plasticity contributes to hypertrophic scar pathogenesis.
The researchers first analyzed freshly excised hypertrophic scar and normal skin (NS) tissues, generating a single-cell atlas of 43,303 dermal cells. This atlas revealed broad disease-related changes in cell composition, including expanded pericytes and reduced total fibroblast abundance. However, one fibroblast subcluster, Fib_5, showed the opposite pattern: it increased markedly in hypertrophic scars and displayed a strong fibrotic phenotype. This subcluster was marked by ADAM12+, COMP+, and POSTN^hi expression and showed increased expression of fibrosis-related genes, including COL1A1, COL1A2, COL3A1, and FN1.
To test whether this finding was reproducible, the team integrated public scRNA-seq datasets comprising 21 additional samples. A Fib_5-like subcluster was again enriched in hypertrophic scars, suggesting that this fibrotic cell state is conserved. Pseudotime analysis placed Fib_5 within an HS-dominant cell-state trajectory, while transcription factor (TF) prediction identified Yin Yang 1 (YY1) as the only candidate TF that was both predicted from branch-specific differentially expressed genes (DEGs) and differentially expressed in the key scar-associated state.
Functional validation strengthened the finding. YY1 expression was reduced in hypertrophic scar fibroblasts. When YY1 was overexpressed in scar-derived fibroblasts, fibrosis-associated proteins, including COL1, COL3, FN1, AKT, and phosphorylated AKT (p-AKT), were reduced. Bulk RNA sequencing, western blotting, immunofluorescence, and Cleavage Under Targets and Tagmentation (CUT&Tag) assays further showed that YY1 restoration could shift fibroblasts away from a fibrotic program. Cell–cell communication analysis also revealed reprogrammed fibroblast–pericyte signaling, suggesting that Fib_5 and pericytes may cooperate in sustaining the fibrotic scar microenvironment.
The authors said the study reframes hypertrophic scars as a disease shaped not only by excessive matrix deposition, but also by a specific fibrotic fibroblast state and its regulatory circuitry. They said Fib_5 appears to act as a central scar-associated fibroblast population, while YY1 functions as a key molecular brake on fibrotic activation. By connecting single-cell mapping with experimental validation, they said the work provides a more precise view of which cells and signals may need to be targeted to interrupt pathological scarring.
These findings may help guide future scar therapies toward more precise, cell-state-specific strategies. YY1 is not yet a clinical treatment target, but the Fib_5–YY1 axis offers a promising direction for mechanistic studies and preclinical testing. The identification of a conserved Fib_5-like population may also support future biomarker development for scar severity, treatment response, or disease progression. In addition, the observed fibroblast–pericyte communication highlights the importance of the scar microenvironment, especially vascular-associated cells, in maintaining fibrosis. Further in vivo studies will be needed to determine whether modulating YY1-related pathways can safely reduce hypertrophic scar formation.
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References
DOI
10.1093/burnst/tkag027
Original Source URL
https://doi.org/10.1093/burnst/tkag027
Funding information
National Natural Science Foundation of China (32370884, 82073468); Chinese Academy of Medical Sciences Initiative for Innovative Medicine (CAMS-I2M) (2021-I2M-1-052).
About Burns & Trauma
Burns & Trauma is an open access, peer-reviewed journal publishing the latest developments in basic, clinical, and translational research related to burns and traumatic injuries, with a special focus on various aspects of biomaterials, tissue engineering, stem cells, critical care, immunobiology, skin transplantation, prevention, and regeneration of burns and trauma injury.