Highlights
- •Role of TRP channels in wound contracture is elucidated using a reconstruction model.
- •Keratinocyte-derived TGF-β1 secretion and fibroblast differentiation are clarified.
- •TRPV2 inhibitors attenuate TGF-β-mediated contraction of the model.
- •TRPV2 channels are markedly expressed in this model.
- •TRPV2 is a possible promising target to ameliorate scar formation.
Abstract
Background
Keratinocytes release several factors that are involved in wound contracture and scar
formation. We previously reported that a three-dimensional reconstruction model derived
from rat skin represents a good wound healing model.
Objective
We characterized the role of transient receptor potential (TRP) channels in the release
of transforming growth factor (TGF)-β1 from keratinocytes and the differentiation
of fibroblasts to identify possible promising pharmacological approaches to prevent
scar formation and contractures.
Methods
The three-dimensional culture model was made from rat keratinocytes seeded on a collagen
gel in which dermal fibroblasts had been embedded.
Results
Among the TRP channel inhibitors tested, the TRPV2 inhibitors SKF96365 and tranilast
attenuated most potently keratinocyte-dependent and — independent collagen gel contraction
due to TGF-β signaling as well as TGF-β1 release from keratinocytes and α-smooth muscle
actin production in myofibroblasts. Besides the low amounts detected in normal dermis,
TRPV2 mRNA and protein levels were increased after fibroblasts were embedded in the
gel. TRPV2 was also expressed in the epidermis and keratinocyte layers of the model.
Both inhibitors and TRPV2 siRNA attenuated the intracellular increase of Ca2+ induced by the TRPV agonist 2-aminoethoxydiphenyl borate in TGF-β1-pretreated fibroblasts.
Conclusion
This is the first study to show that compounds targeting TRPV2 channels ameliorate
wound contraction through the inhibition of TGF-β1 release and the differentiation
of dermal fibroblasts in a culture model.
Keywords
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References
- Novel therapies for scar reduction and regenerative healing of skin wounds.Trends Biotechnol. 2008; 26: 173-180
- Myofibroblasts and mechano-regulation of connective tissue remodelling.Nat. Rev. Mol. Cell Biol. 2002; 3: 349-363
- α-Smooth muscle actin is transiently expressed by myofibroblasts during experimental wound healing.Lab. Invest. 1990; 63: 21-29
- Regulation of α-smooth muscle actin gene expression in myofibroblast differentiation from rat lung fibroblasts.Int. J. Biochem. Cell Biol. 2001; 33: 723-734
- New developments in fibroblast and myofibroblast biology: implications for fibrosis and scleroderma.Curr. Rheumatol. Rep. 2007; 9: 136-143
- Transforming growth factor-β1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts.J. Cell Biol. 1993; 122: 103-111
- Injury induced expression of TGF-β1 mRNA is enhanced by exogenously applied TGF-βs.Biochem. Biophys. Res. Commun. 1993; 194: 399-406
- Healing of burn wounds in transgenic mice overexpressing transforming growth factor-β1 in the epidermis.Am. J. Pathol. 2001; 159: 2147-2157
- Proteolytic and non-proteolytic activation of keratinocyte-derived latent TGF-β1 induces fibroblast differentiation in a wound-healing model using rat skin.J. Pharmacol. Sci. 2014; 124: 230-243
- TRPV1 potentiates TGFβ-induction of corneal myofibroblast development through an oxidative stress-mediated p38-SMAD2 signaling loop.PLoS One. 2013; 8: e77300
- TRPV4 channels mediate cardiac fibroblast differentiation by integrating mechanical and soluble signals.J. Mol. Cell. Cardiol. 2013; 54: 45-52
- TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice.J. Clin. Invest. 2014; 124: 5225-5238
- TRPA1 is required for TGF-β signaling and its loss blocks inflammatory fibrosis in mouse corneal stroma.Lab. Invest. 2014; 94: 1030-1041
- Hypertrophic scar contracture is mediated by the TRPC3 mechanical force transducer via NFkB activation.Sci. Rep. 2015; 5: 11620
- A TRPC6-dependent pathway for myofibroblast transdifferentiation and wound healing in vivo.Dev. Cell. 2012; 23: 705-715
- Intestinal myofibroblast TRPC6 channel may contribute to stenotic fibrosis in Crohn's disease.Inflamm. Bowel Dis. 2015; 21: 496-506
- TRPM7-mediated Ca2+ signals confer fibrogenesis in human atrial fibrillation.Circ. Res. 2010; 106: 992-1003
- The thermosensitive TRPV3 channel contributes to rapid wound healing in oral epithelia.FASEB J. 2015; 29: 182-192
- The TRPV4 channel contributes to intercellular junction formation in keratinocytes.J. Biol. Chem. 2010; 285: 18749-18758
- Keratinocyte regulation of TGF-β and connective tissue growth factor expression: A role in suppression of scar tissue formation.Wound Repair Regen. 2007; 15: 748-755
- Animal models for wound repair.Arch. Dermatol. Res. 1998; 290: S1-S11
- Pharmacological characterization and molecular determinants of the activation of transient receptor potential V2 channel orthologs by 2-aminoethoxydiphenyl borate.Mol. Pharmacol. 2007; 72: 1258-1268
- Inhibition of proliferation of MCF-7 breast cancer cells by a blocker of Ca2+-permeable channel.Cell Calcium. 1997; 22: 75-82
- Regulation of calcium-permeable TRPV2 channel by insulin in pancreatic β-cells.Diabetes. 2009; 58: 174-184
- Involvement of TRPV2 activation in intestinal movement through nitric oxide production in mice.J. Neurosci. 2010; 30: 16536-16544
- Selective inhibition of collagen accumulation by N-(3,4-dimethoxycinnamoyl)anthranilic acid (N-5') in granulation tissue.Biochem. Pharmacol. 1987; 36: 469-474
- The mechanism involved in the inhibitory action of tranilast on collagen biosynthesis of keloid fibroblasts.Jpn. J. Pharmacol. 1992; 60: 91-96
- A capsaicin-receptor homologue with a high threshold for noxious heat.Nature. 1999; 398: 436-441
- What do we know about the transient receptor potential vanilloid 2 (TRPV2) ion channel.FEBS J. 2013; 280: 5471-5487
- Physiological significance of TRPV2 as a mechanosensor, thermosensor and lipid sensor.J. Physiol. Sci. 2016; 66: 359-365
- Activation of TRPV2 negatively regulates the differentiation of mouse brown adipocytes.Pfluger’s Arch. 2016; 468: 1527-1540
- Cannabidiol enhances microglial phagocytosis via transient receptor potential (TRP) channel activation.Br. J. Pharmacol. 2014; 171: 2426-2439
- Mechanosensitive Ca2⁺-permeable channels in human leukemic cells: pharmacological and molecular evidence for TRPV2.Biochim. Biophys. Acta. 1848; 2015: 51-59
- Selective potentiation of 2-APB-induced activation of TRPV1-3 channels by acid.Sci. Rep. 2016; 6: 20791
- Transient receptor potential vanilloid 1 activation induces inflammatory cytokine release in corneal epithelium through MAPK signaling.J. Cell. Physiol. 2007; 213: 730-739
- TRPV4 and KCa ion channels functionally couple as osmosensors in the paraventricular nucleus.Br. J. Pharmacol. 2015; 172: 1753-1768
- TRPV4 regulates the integrity of the blood-cerebrospinal fluid barrier and modulates transepithelial protein transport.FASEB J. 2015; 29: 2247-2259
- Functional TRPV2 and TRPV4 channels in human cardiac c-kit+ progenitor cells.J. Cell. Mol. Med. 2016; 20: 1118-1127
- TRPV2 Channels Contribute to Stretch-Activated Cation Currents and Myogenic Constriction in Retinal Arterioles.Invest. Ophthalmol. Vis. Sci. 2016; 57: 5637-5647
- Bone marrow stromal cells preadipocytes, and dermal fibroblasts promote epidermal regeneration in their distinctive fashions.Mol. Biol. Cell. 2004; 15: 4647-4657
- TRP Channels in Skin Biology and Pathophysiology.Pharmaceuticals. 2016; 9: 77
- A critical role of serum response factor in myofibroblast differentiation during experimental oesophageal ulcer healing in rats.Gut. 2007; 56: 621-630
- Critical role of serum response factor in pulmonary myofibroblast differentiation induced by TGF-β.Am. J. Respir. Cell Mol. Biol. 2009; 41: 332-338
- Keratinocyte-fibroblast interactions in wound healing.J. Invest. Dermatol. 2007; 127: 998-1008
- Interactions between myofibroblast differentiation and epidermogenesis in constructing human living skin equivalents.J. Dermatol. Sci. 2012; 65: 50-57
- Transient receptor potential channels in mechanosensing and cell volume regulation.in: Häussinger D. Sies H. Methods in Enzymology 428 Osmosensing and Osmosignaling. Elsevier Inc., Netherlands2007: 183-207
- Pharmacology of vanilloid transient receptor potential cation channels.Mol. Pharmacol. 2009; 75: 1262-1279
- TRPV2 is a component of osmotically sensitive cation channels in murine aortic myocytes.Circ. Res. 2003; 93: 829-838
- TRPV2 enhances axon outgrowth through its activation by membrane stretch in developing sensory and motor neurons.J. Neurosci. 2010; 30: 4601-4612
Article info
Publication history
Published online: March 06, 2018
Accepted:
March 1,
2018
Received in revised form:
February 27,
2018
Received:
January 9,
2018
Identification
Copyright
© 2018 Published by Elsevier B.V. on behalf of Japanese Society for Investigative Dermatology.