Comprehensive analysis of skin growth-related hub genes and microenvironment characterization in a mouse expanded skin model

Front Immunol. 2024 Dec 5:15:1306353. doi: 10.3389/fimmu.2024.1306353. eCollection 2024.

Abstract

Background: Mechanical stretch-mediated tissue expansion is effective for obtaining extra skin and soft tissue required for the repair of defects or reconstruction of surface organs. Understanding the cellular and molecular mechanisms and identifying hub genes and key cell types associated with skin expansion could help predict the success of skin growth during expansion procedures.

Methods: We analyzed murine chip sequencing data and single-cell sequencing data available from the Gene Expression Omnibus database. Based on the differentially expressed and epithelial-mesenchymal transition-related genes, random forest and protein-protein interaction network analysis identified hub genes for predicting skin regeneration in tissue expansion. The fate of the cell subpopulations, expression of hub genes in different cell types, and their communication were also assessed.

Results: Five genes, integrin beta 5 (Itgb5), tropomyosin 1 (Tpm1), secreted frizzled-related protein-1 (Sfrp1), Notch1, and insulin-like growth factor binding protein 2 (Igfbp2), were identified as having the greatest impact on prediction accuracy. These hub genes were primarily enriched in the Notch and phosphoinositide 3-kinase-AKT pathways. Immune cell infiltration analysis further revealed that mast cell infiltration was significantly higher in the expanded skin group than that in the control group. According to single-cell data, the interactions between epithelial cells, stem cells, and other cell types were higher in the expanded skin group than those in the control group. Moreover, Tpm1, Sfrp1, and Notch1 were highly expressed in all epithelial and stem cell subgroups.

Conclusions: The hub genes, Notch1, Tpm1 and Sfrp1, and their associated signaling pathways such as Notch and Wnt signaling and functions in key cell subsets highlight prospective therapeutic strategies to enhance skin growth under mechanical expansion. Moreover, mast cell activation and infiltration may trigger immune responses in the expanded skin, which requires further investigation.

Keywords: hub genes; mast cell (MC); microenvironment; skin regeneration; tissue expansion.

MeSH terms

  • Animals
  • Cellular Microenvironment / genetics
  • Epithelial-Mesenchymal Transition / genetics
  • Gene Expression Profiling
  • Gene Regulatory Networks
  • Mast Cells / immunology
  • Mast Cells / metabolism
  • Mice
  • Protein Interaction Maps
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism
  • Regeneration / genetics
  • Single-Cell Analysis
  • Skin* / metabolism
  • Transcriptome
  • Tropomyosin / genetics
  • Tropomyosin / metabolism

Substances

  • Receptor, Notch1
  • Tropomyosin
  • Notch1 protein, mouse

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was funded by the National Nature Science Youth Foundation of China (82402938 & 82102354), and Clinical Research Program of 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine (JYLJ202104), Wuxi Taihu Lake Talent Plan, Supports for Leading Talents in Medical and Health Profession, and Shanghai Clinical Research Center of Plastic and Reconstructive Surgery supported by Science and Technology Commission of Shanghai Municipality (Grant No. 22MC1940300). The funding body did not play a role in the study design, data collection, analyses, and interpretation, manuscript preparation, and in the decision to submit the manuscript.