Myofibroblasts in murine cutaneous fibrosis originate from adiponectin-positive intradermal progenitors
Open accessAbstract
Objective: Accumulation of myofibroblasts in fibrotic skin is a hallmark of systemic sclerosis (SSc; scleroderma), but the origins of these cells remain unknown. Because loss of intradermal adipose tissue is a consistent feature of cutaneous fibrosis, we sought to examine the hypothesis that myofibroblasts populating fibrotic dermis derive from adipocytic progenitors. Methods: We performed genetic fate mapping studies to investigate the loss of intradermal adipose tissue and its potential role in fibrosis in mice with bleomycin‐induced scleroderma. Modulation of adipocytic phenotypes ex vivo was investigated in adipose tissue–derived cells in culture. Results: A striking loss of intradermal adipose tissue and its replacement with fibrous tissue were consistently observed in mice with bleomycin‐induced fibrosis. Loss of adipose tissue and a decline in the expression of canonical adipogenic markers in lesional skin preceded the onset of dermal fibrosis and expression of fibrogenic markers. Ex vivo, subcutaneous adipocytes were driven by transforming growth factor β to preferentially undergo fibrogenic differentiation. Cell fate mapping studies in mice with the adiponectin promoter–driven Cre recombinase transgenic construct indicated that adiponectin‐positive progenitors that are normally confined to the intradermal adipose tissue compartment were distributed throughout the lesional dermis over time, lost their adipocytic markers, and expressed myofibroblast markers in bleomycin‐treated mice. Conclusion: These observations establish a novel link between intradermal adipose tissue loss and dermal fibrosis and demonstrate that adiponectin‐positive intradermal progenitors give rise to dermal myofibroblasts. Adipose tissue loss and adipocyte–myofibroblast transition might be primary events in the pathogenesis of cutaneous fibrosis that represent novel potential targets for therapeutic intervention.
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Adipocytes are another source of myofibroblasts in SSc.
“In addition to the abovementioned cells, adipocytes, i.e., fat cells, are another source of myofibroblasts in SSc.”
From Unraveling SSc Pathophysiology; The Myofibroblast (2018) · cites this paper as [88]
Adipocyte to myofibroblast transition is strongly driven by TGFβ, FIZZ1, and possibly Wnt signaling.
“Adipocyte to myofibroblast transition is strongly driven by TGFβ (88), Found in inflammatory zone 1 (FIZZ1) and possibly Wnt signaling (89).”
From Unraveling SSc Pathophysiology; The Myofibroblast (2018) · cites this paper as [88]
In the murine bleomycin model of skin fibrosis, loss of fat tissue precedes fibrosis, indicating that adipocyte to myofibroblast transition can underlie the fibrotic process.
“Importantly, in this model of skin fibrosis the loss of fat tissue precedes fibrosis (88) indicating that this process can underlie the fibrotic process.”
From Unraveling SSc Pathophysiology; The Myofibroblast (2018) · cites this paper as [88]
In SSc skin, subcutaneous fat disappears over the course of the disease.
“In SSc skin, subcutaneous fat disappears over the course of the disease (88).”
From Unraveling SSc Pathophysiology; The Myofibroblast (2018) · cites this paper as [88]
Via the process of adipocyte to myofibroblast transition, adipocytes can become myofibroblasts.
“Via the process of adipocyte to myofibroblast transition these cells can become myofibroblasts.”
From Unraveling SSc Pathophysiology; The Myofibroblast (2018) · cites this paper as [88]
In the murine bleomycin model of skin fibrosis, adipocytes can lose their adipocyte-related gene expression and start expressing αSMA to become myofibroblasts.
“With the use of adiponectin-lineage tracking, it has been demonstrated in the murine bleomycin model of skin fibrosis that adipocytes can lose their adipocyte-related gene expression and start expressing αSMA to become myofibroblasts (88).”
From Unraveling SSc Pathophysiology; The Myofibroblast (2018) · cites this paper as [88]
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References 50 · Cited by 337
- Authors
- Marangoni, R. G., Korman, B. D., Wei, J., Wood, T. A., Graham, L. V., Whitfield, M. L., Scherer, P. E., Tourtellotte, W. G., & Varga, J.
- Affiliations
- Northwestern University Feinberg School of Medicine Chicago Illinois
- Northwestern University (US)
- Dartmouth College (US)
- The University of Texas Southwestern Medical Center (US)
- ORCID
- Venue
- Arthritis & Rheumatology
- Publisher
- Wiley
- Published
- 2015-03-27
- Volume
- 67
- Issue
- 4
- Pages
- 1062-1073
- ISSN
- 2326-5191 (ISSN-L)
- 2326-5205
- PMC
- PMC4472310
- OpenAlex
- W1558442378
- Cited by
- 337
- References
- 50
- Citations by year
- 2026: 19 · 2025: 23 · 2024: 30 · 2023: 26 · 2022: 34 · 2021: 37 · 2020: 26 · 2019: 36 · 2018: 35 · 2017: 33 · 2016: 23 · 2015: 13 · 2014: 1 · 2013: 1
- FWCI
- 17.32
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Arthritis & Rheumatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Northwestern University
- National Institutes of Health (K26OD010945)
- National Cancer Institute (CA 060553, P30CA060553)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR 42309, R01AR042309, P30AR061271, R56AR042309, T32AR060710)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD055884)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Systemic Sclerosis and Related Diseases
- Health Sciences › Medicine › Rheumatology › Dupuytren's Contracture and Treatments
- Health Sciences › Medicine › Dermatology › Cutaneous lymphoproliferative disorders research
- Keywords
- myofibroblasts, skin fibrosis, systemic sclerosis, adiponectin, bleomycin-induced fibrosis, TGF-beta, cell fate mapping
- MeSH terms
- Animals, Bleomycin, Disease Models, Animal, Fibrosis, Scleroderma, Systemic, Skin, Skin Diseases, Adipocytes, Cell Lineage, Mice, Adiponectin, Myofibroblasts
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