TRPV4 ion channel is a novel regulator of dermal myofibroblast differentiation
Open accessAbstract
Scleroderma is a multisystem fibroproliferative disease with no effective medical treatment. Myofibroblasts are critical to the fibrogenic tissue repair process in the skin and many internal organs. Emerging data support a role for both matrix stiffness, and transforming growth factor β1 (TGFβ1), in myofibroblast differentiation. Transient receptor potential vanilloid 4 (TRPV4) is a mechanosensitive ion channel activated by both mechanical and biochemical stimuli. The objective of this study was to determine the role of TRPV4 in TGFβ1- and matrix stiffness-induced differentiation of dermal fibroblasts. We found that TRPV4 channels are expressed and functional in both human (HDF) and mouse (MDF) dermal fibroblasts. TRPV4 activity (agonist-induced Ca2+ influx) was induced by both matrix stiffness and TGFβ1 in dermal fibroblasts. TGFβ1 induced expression of TRPV4 proteins in a dose-dependent manner. Genetic ablation or pharmacological antagonism of TRPV4 channel abrogated Ca2+ influx and both TGFβ1-induced and matrix stiffness-induced myofibroblast differentiation as assessed by 1) α-smooth muscle actin expression/incorporation into stress fibers, 2) generation of polymerized actin, and 3) expression of collagen-1. We found that TRPV4 inhibition abrogated TGFβ1-induced activation of AKT but not of Smad2/3, suggesting that the mechanism by which profibrotic TGFβ1 signaling in dermal fibroblasts is modified by TRPV4 may be through non-Smad pathways. Altogether, these data identify a novel reciprocal functional link between TRPV4 activation and TGFβ1 signals regulating dermal myofibroblast differentiation. These findings suggest that therapeutic inhibition of TRPV4 activity may provide a targeted approach to the treatment of scleroderma.
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TRPV4 can activate TGF-β1/AKT signal and enhance differentiation of dermal myofibroblasts and increase in collagen content induced by TGF-β1.
“Furthermore, TRPV4 can activate the TGF-β1/AKT signal and enhance the differentiation of dermal myofibroblasts and the increase in collagen content induced by TGF-β1 [95] (Figure 1).”
From Boosting the Photoaged Skin: The Potential Role of Dietary Components (2021) · cites this paper as [95]
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Contribution of mechanical homeostasis to epithelial-mesenchymal transition
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Engineering Advanced In Vitro Models of Systemic Sclerosis for Drug Discovery and Development
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The role of TRPV4 channels in cutaneous epithelia
Moore, C. D. (2022) · Current topics in membranes · doi:10.1016/bs.ctm.2022.06.003 · Cited by 20 · see citing works
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Self-citationMechanisms underlying divergent relationships between Ca2+ and YAP/TAZ signalling
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Macrophage microRNA-146a is a central regulator of the foreign body response to biomaterial implants
Mahanty, M., Dutta, B., Ou, W., Zhu, X., Bromberg, J. S., He, X., & Rahaman, S. O. (2024) · Biomaterials · doi:10.1016/j.biomaterials.2024.122855 · Cited by 16 · see citing works
Self-citationTRPV4 activation by TGFβ2 enhances cellular contractility and drives ocular hypertensionPreprint
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Molecular signaling in biomaterial-induced foreign body response: current perspectives
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Transient stimulation of TRPV4‐expressing keratinocytes promotes hair follicle regeneration in mice
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Comparative Analysis of Single-Molecule Dynamics of TRPV1 and TRPV4 Channels in Living Cells
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Self-citationEmerging roles of mechanically activated ion channels in autoimmune disease
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Coeyman, S. J., Richardson, W. J., & Bradshaw, A. D. (2022) · Current Opinion in Physiology · doi:10.1016/j.cophys.2022.100560 · Cited by 8 · see citing works
TRPV4 mediates IL ‐1‐induced Ca 2+ signaling, ERK activation and MMP expression
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Role of TRPV4 Channel in Human White Adipocytes Metabolic Activity
Sánchez, J. C., Valencia-Vásquez, A., & García, A. M. (2021) · Endocrinology and Metabolism · doi:10.3803/enm.2021.1167 · Cited by 8 · see citing works
The roles of transient receptor potential vanilloid in autoimmune diseases
Xiao, Y., Yue, X., Shen, K., Yang, M., & Wu, H. (2025) · Autoimmunity Reviews · doi:10.1016/j.autrev.2025.103872 · Cited by 8 · see citing works
TRPV4 activation in Schwann cells mediates mechanically induced pain of oral cancer
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Role of TRPV4 in matrix stiffness-induced expression of EMT-specific LncRNA
Sharma, S., Ma, L., & Rahaman, S. O. (2020) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-020-03844-1 · Cited by 7 · see citing works
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DAMP-Promoted Efferent Innate Immune Responses in Human Diseases: Fibrosis
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In vitro evidence on photobiomodulation by blue LED light
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Self-citationA novel role for TRPV1 in macrophage giant cell formation
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Self-citationEngineered models of skin fibrosis: from biomaterial-free to biomaterial-based in vitro systems
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- Authors
- Sharma, S., Goswami, R., Merth, M., Cohen, J., Lei, K. Y., Zhang, D. X., & Rahaman, S. O.
- Affiliations
- University of Maryland, College Park (US)
- Medical College of Wisconsin (US)
- Corresponding author
- Rahaman, Shaik O.
- Venue
- American Journal of Physiology-Cell Physiology
- Publisher
- American Physiological Society
- Published
- 2017-05-01
- Volume
- 312
- Issue
- 5
- Pages
- C562-C572
- ISSN
- 0363-6143 (ISSN-L)
- 1522-1563
- PMC
- PMC6105932
- OpenAlex
- W2592906727
- Cited by
- 90
- References
- 56
- Citations by year
- 2026: 10 · 2025: 19 · 2024: 6 · 2023: 4 · 2022: 11 · 2021: 9 · 2020: 14 · 2019: 10 · 2018: 5 · 2017: 2
- FWCI
- 5.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Cell Physiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association (AHA) (13SDG17310007)
- Topics
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Health Sciences › Medicine › Pathology and Forensic Medicine › Systemic Sclerosis and Related Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- TRPV4, myofibroblast differentiation, systemic sclerosis, TGF-β1 signaling, extracellular matrix stiffness, mechanosensitive ion channels, calcium influx, dermal fibroblasts, Akt signaling, collagen-1, alpha-smooth muscle actin, actin polymerization, skin fibrosis
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Extracellular Matrix, Humans, Mice, Inbred C57BL, Skin, Species Specificity, Ion Channel Gating, Mice, Knockout, Gene Expression Regulation, Developmental, Mechanotransduction, Cellular, TRPV Cation Channels, Mice, Transforming Growth Factor beta1, Elastic Modulus, Myofibroblasts
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