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Published on: November 16, 2011
Heterogeneous response to TGF-β1/3 isoforms in fibroblasts of different origins: implications for wound healing and
Lukáš Urban1,2, Matúš Čoma1,2, Lukáš Lacina3,4,5
1Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, 040 11, Košice, Slovak Republic.
Abstract:
Identification of therapeutic targets for treating fibrotic diseases and cancer remains challenging. Our study aimed to investigate the effects of TGF-β1 and TGF-β3 on myofibroblast differentiation and extracellular matrix deposition in different types of fibroblasts, including normal/dermal, cancer-associated, and scar-derived fibroblasts. When comparing the phenotype and signaling pathways activation we observed extreme heterogeneity of studied markers across different fibroblast populations, even within those isolated from the same tissue. Specifically, the presence of myofibroblast and deposition of extracellular matrix were dependent on the origin of the fibroblasts and the type of treatment they received (TGF-β1 vs. TGF-β3). In parallel, we detected activation of canonical signaling (pSMAD2/3) across all studied fibroblasts, albeit to various extents. Treatment with TGF-β1 and TGF-β3 resulted in the activation of canonical and several non-canonical pathways, including AKT, ERK, and ROCK. Among studied cells, cancer-associated fibroblasts displayed the most heterogenic response to TGF-β1/3 treatments. In general, TGF-β1 demonstrated a more potent activation of signaling pathways compared to TGF-β3, whereas TGF-β3 exhibited rather an inhibitory effect in keloid- and hypertrophic scar-derived fibroblasts suggesting its clinical potential for scar treatment. In summary, our study has implications for comprehending the role of TGF-β signaling in fibroblast biology, fibrotic diseases, and cancer. Future research should focus on unraveling the mechanisms beyond differential fibroblast responses to TGF-β isomers considering inherent fibroblast heterogeneity.
Insights
Transforming growth factor-beta (TGF-β) isomers differentially regulate fibroblast behavior. TGF-β3 shows potential for scar treatment by inhibiting fibroblast activity, unlike TGF-β1.
Area of Science:
- Cell Biology
- Biochemistry
- Molecular Biology
Background:
- Therapeutic target identification for fibrotic diseases and cancer is challenging.
- Fibroblast heterogeneity complicates understanding of disease mechanisms.
Purpose of the Study:
- Investigate TGF-β1 and TGF-β3 effects on myofibroblast differentiation and extracellular matrix deposition.
- Analyze responses in normal, cancer-associated, and scar-derived fibroblasts.
Main Methods:
- Compared fibroblast phenotypes and signaling pathway activation.
- Utilized TGF-β1 and TGF-β3 treatments.
- Analyzed canonical (pSMAD2/3) and non-canonical (AKT, ERK, ROCK) pathways.
Main Results:
- Observed significant heterogeneity in fibroblast responses to TGF-β isomers.
- TGF-β1 generally showed more potent signaling activation than TGF-β3.
- TGF-β3 exhibited inhibitory effects on scar-derived fibroblasts, suggesting therapeutic potential.
Conclusions:
- Fibroblast responses to TGF-β isomers are highly dependent on cell origin and treatment type.
- TGF-β signaling heterogeneity impacts fibrotic diseases and cancer.
- TGF-β3 warrants further investigation for clinical applications in scar treatment.
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