2. Academic Validation
  3. Multi-omic analysis reveals retinoic acid molecular drivers for dermal fibrosis and regenerative repair in the skin

Multi-omic analysis reveals retinoic acid molecular drivers for dermal fibrosis and regenerative repair in the skin

  • Cell Stem Cell. 2025 Sep 4;32(9):1421-1437.e6. doi: 10.1016/j.stem.2025.07.010.
Michelle Griffin 1,  Jason L Guo 1,  Jennifer B L Parker 2,  Maxwell Kuhnert 1,  Dayan J Li 1,  Caleb Valencia 1,  Annah Morgan 1,  Mauricio Downer 1,  Asha C Cotterell 1,  John M Lu 2,  Sarah Dilorio 3,  Khristian Eric Bauer-Rowe Ramos 3,  Michael Januszyk 2,  Howard Y Chang 4,  Derrick C Wan 5,  Michael T Longaker 6
Affiliations

Affiliations

  • 1 Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 2 Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 3 Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 4 Department of Dermatology and Genetics, Stanford University School of Medicine, Stanford, CA, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
  • 5 Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: dwan@stanford.edu.
  • 6 Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: longaker@stanford.edu.
PMID: 40816279 DOI: 10.1016/j.stem.2025.07.010
Abstract

Skin fibrosis is driven by fibroblast activation and excessive extracellular matrix deposition. To ascertain the fibroblast subpopulation(s) responsible for instigating fibrosis, we employed an established murine bleomycin skin fibrosis model. We characterized both the fibrotic and remodeling phases of dermal fibrosis through a multi-omic approach. Using an unsupervised machine learning algorithm that quantifies 294 fiber features, we identified precise time points of fibrosis and regeneration. Single-cell transcriptomic and epigenomic Sequencing then identified a Cyp26b1-expressing fibroblast subpopulation responsible for dermal fibrosis. The same fibroblast subtype was mapped to Visium spatial transcriptomic data. We further mapped the fibrotic subtypes to protein spatial data. To ascertain the functional impact of the fibroblast subpopulations, transplant delivery analysis showed their ability to drive skin fibrosis. Lastly, we identified a small molecular inhibitor of Cyp26b1 (talarozole) that prevents and rescues dermal fibrosis. Conclusively, we establish an atlas of the fibrotic and regenerative biological drivers of skin fibrosis.

Keywords

Cyp26b1; fibroblasts; multi-omic; retinoic acid; single-cell sequencing; skin fibrosis; spatial transcriptomic; transcriptomics; vitamin A; wound healing.

Figures
Products