Single-cell analysis reveals fibroblast heterogeneity and myeloid-derived adipocyte progenitors in murine skin wounds
Open accessAbstract
During wound healing in adult mouse skin, hair follicles and then adipocytes regenerate. Adipocytes regenerate from myofibroblasts, a specialized contractile wound fibroblast. Here we study wound fibroblast diversity using single-cell RNA-sequencing. On analysis, wound fibroblasts group into twelve clusters. Pseudotime and RNA velocity analyses reveal that some clusters likely represent consecutive differentiation states toward a contractile phenotype, while others appear to represent distinct fibroblast lineages. One subset of fibroblasts expresses hematopoietic markers, suggesting their myeloid origin. We validate this finding using single-cell western blot and single-cell RNA-sequencing on genetically labeled myofibroblasts. Using bone marrow transplantation and Cre recombinase-based lineage tracing experiments, we rule out cell fusion events and confirm that hematopoietic lineage cells give rise to a subset of myofibroblasts and rare regenerated adipocytes. In conclusion, our study reveals that wounding induces a high degree of heterogeneity among fibroblasts and recruits highly plastic myeloid cells that contribute to adipocyte regeneration.
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Old mice exhibit variability in wound healing rates in vivo, and single-cell RNA sequencing identified distinct fibroblast subpopulations with differing cytokine expression profiles in wounds of old mice with slow versus fast healing rates.
“Old mice exhibited variability in wound healing rates in vivo, and scRNASeq identified distinct subpopulations of fibroblasts with differing cytokine expression profiles in the wounds of old mice with slow versus fast healing rates.”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [34]
Increasing age drives fibroblast functional heterogeneity, with old fibroblasts showing variability in their ability to reprogram and heal wounds.
“Increasing age is a driver of fibroblast functional heterogeneity, with ‘old’ fibroblasts demonstrating variability in their ability to reprogram and heal wounds34 .”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [34]
Increased variability in wound healing with age may reflect distinct stochastic ageing trajectories between individuals, which should be considered when designing personalized antifibrotic therapies for the elderly.
“This increased variability in wound healing with increasing age may reflect distinct stochastic ageing trajectories between individuals, which will need to be considered when designing personalized antifibrotic therapies for the elderly population34.”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [34]
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Herum, K. M., Weng, G., Kahnert, K., Waikel, R., Milburn, G., Conger, A., Anaya, P., Campbell, K. S., Lundby, A., Won, K. J., et al. (2022) · Matrix Biology Plus · doi:10.1016/j.mbplus.2022.100113 · Cited by 15 · see citing works
Expression quantitative trait locus studies in the era of single-cell omics
Luo, J., Wu, X., Cheng, Y., Chen, G., Wang, J., & Song, X. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2023.1182579 · Cited by 11 · see citing works
- Authors
- Guerrero-Juarez, C. F., Dedhia, P. H., Jin, S., Ruiz-Vega, R., Ma, D., Liu, Y., Yamaga, K., Shestova, O., Gay, D. L., Yang, Z., Kessenbrock, K., Nie, Q., Pear, W. S., Cotsarelis, G., & Plikus, M. V.
- Affiliations
- University of Pennsylvania (US)
- University of California, Irvine (US)
- Inserm (FR)
- Corresponding author
- Cotsarelis, George
- Plikus, Maksim V.
- ORCID
- Venue
- Nature Communications
- Published
- 2019-02-08
- Volume
- 10
- Issue
- 1
- Pages
- 650-650
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6368572
- OpenAlex
- W2911253006
- Cited by
- 521
- References
- 70
- Citations by year
- 2026: 55 · 2025: 56 · 2024: 92 · 2023: 71 · 2022: 91 · 2021: 76 · 2020: 57 · 2019: 22
- FWCI
- 42.95
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Science Foundation (1562176, 594598, 1321846, DMS176‐3272, 1763272)
- LEO Fondet (LF18099)
- National Institutes of Health (DGE-1321846, 594598, DMS1562176, DMS 1763272)
- Canadian Institutes of Health Research
- National Institute of General Medical Sciences (R25GM055246)
- National Institute of Allergy and Infectious Diseases (R01AI047833)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR055309, U01AR073159, P30AR057217, R01AR069653, R01AR067273)
- Center for Complex Biological Systems, University of California, Irvine
- Topics
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Planarian Biology and Electrostimulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- wound healing, skin wounds, fibroblast heterogeneity, myofibroblasts, fibroblast differentiation, cell fusion, lineage tracing, single-cell RNA sequencing, pseudotime, RNA velocity
- MeSH terms
- Animals, Cells, Cultured, Female, Fibroblasts, Male, Skin, Stem Cells, Wound Healing, Blotting, Western, Sequence Analysis, RNA, Adipocytes, Mice, Single-Cell Analysis
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