Dataset Information

Semaphorin 3A potentiates the profibrotic effects of transforming growth factor-?1 in the cornea.

ABSTRACT: Corneal scarring is a major cause of blindness worldwide with few effective therapeutic options. Finding a treatment would be of tremendous public health benefit, but requires a thorough understanding of the complex interactions that underlie this phenomenon. Here, we tested the hypothesis that the large increase in expression of Semaphorin 3A (SEMA3A) in corneal wounds contributes to the development of stromal fibrosis. We first verified this increased expression in vivo, in a cat model of photorefractive keratectomy-induced corneal wounding. We then examined the impact of adding exogenous SEMA3A to cultured corneal fibroblasts, and assessed how this affected the ability of transforming growth factor-beta1 (TGF-?1) to induce their differentiation into myofibroblasts. Finally, we examined how siRNA knockdown of endogenous SEMA3A affected these same phenomena. We found exogenous SEMA3A to significantly potentiate TGF-?1's profibrotic effects, with only a minimal contribution from cell-intrinsic SEMA3A. Our results suggest a previously unrecognized interaction between SEMA3A and TGF-?1 in the wounded cornea, and a possible contribution of SEMA3A to the regulation of tissue fibrosis and remodeling in this transparent organ.

SUBMITTER: Jeon KI

PROVIDER: S-EPMC6935409 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Semaphorin 3A potentiates the profibrotic effects of transforming growth factor-β1 in the cornea.

Jeon Kye-Im KI Nehrke Keith K Huxlin Krystel R KR

Biochemical and biophysical research communications 20191024 2

Corneal scarring is a major cause of blindness worldwide with few effective therapeutic options. Finding a treatment would be of tremendous public health benefit, but requires a thorough understanding of the complex interactions that underlie this phenomenon. Here, we tested the hypothesis that the large increase in expression of Semaphorin 3A (SEMA3A) in corneal wounds contributes to the development of stromal fibrosis. We first verified this increased expression in vivo, in a cat model of phot ...[more]

PMID: 31668808

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Project description:Embryonic heart valve primordia (cushions) maintain unidirectional blood flow during development despite an increasingly demanding mechanical environment. Recent studies demonstrate that atrioventricular (AV) cushions stiffen over gestation, but the molecular mechanisms of this process are unknown. Transforming growth factor-beta (TGFβ) and serotonin (5-HT) signaling modulate tissue biomechanics of postnatal valves, but less is known of their role in the biomechanical remodeling of embryonic valves. In this study, we demonstrate that exogenous TGFβ3 increases AV cushion biomechanical stiffness and residual stress, but paradoxically reduces matrix compaction. We then show that TGFβ3 induces contractile gene expression (RhoA, aSMA) and extracellular matrix expression (col1α2) in cushion mesenchyme, while simultaneously stimulating a two-fold increase in proliferation. Local compaction increased due to an elevated contractile phenotype, but global compaction appeared reduced due to proliferation and ECM synthesis. Blockade of TGFβ type I receptors via SB431542 inhibited the TGFβ3 effects. We next showed that exogenous 5-HT does not influence cushion stiffness by itself, but synergistically increases cushion stiffness with TGFβ3 co-treatment. 5-HT increased TGFβ3 gene expression and also potentiated TGFβ3 induced gene expression in a dose-dependent manner. Blockade of the 5HT2b receptor, but not 5-HT2a receptor or serotonin transporter (SERT), resulted in complete cessation of TGFβ3 induced mechanical strengthening. Finally, systemic 5-HT administration in ovo induced cushion remodeling related defects, including thinned/atretic AV valves, ventricular septal defects, and outflow rotation defects. Elevated 5-HT in ovo resulted in elevated remodeling gene expression and increased TGFβ signaling activity, supporting our ex-vivo findings. Collectively, these results highlight TGFβ/5-HT signaling as a potent mechanism for control of biomechanical remodeling of AV cushions during development.

Dataset Information

Semaphorin 3A potentiates the profibrotic effects of transforming growth factor-?1 in the cornea.

Publications

Semaphorin 3A potentiates the profibrotic effects of transforming growth factor-β1 in the cornea.

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