Abstract
The antifibrotic potential of platelet-rich plasma (PRP) is controversial. This study examined the effects of PRP on in vitro transforming growth factor (TGF)-β1-induced differentiation of fibroblasts into myofibroblasts, the main drivers of fibrosis, and the involvement of vascular endothelial growth factor (VEGF)-A in mediating PRP-induced responses. The impact of PRP alone on fibroblast differentiation was also assessed. Myofibroblastic phenotype was evaluated by confocal fluorescence microscopy and western blotting analyses of α-smooth muscle actin (sma) and type-1 collagen expression, vinculin-rich focal adhesion clustering, and stress fiber assembly. Notch-1, connexin 43, and VEGF-A expression were also analyzed by RT-PCR. PRP negatively regulated fibroblast-myofibroblast transition via VEGF-A/VEGF receptor (VEGFR)-1-mediated inhibition of TGF-β1/Smad3 signaling. Indeed TGF-β1/PRP co-treated fibroblasts showed a robust attenuation of the myofibroblastic phenotype concomitant with a decrease of Smad3 expression levels. The VEGFR-1 inhibition by KRN633 or blocking antibodies, or VEGF-A neutralization in these cells prevented the PRP-promoted effects. Moreover PRP abrogated the TGF-β1-induced reduction of VEGF-A and VEGFR-1 cell expression. The role of VEGF-A signaling in counteracting myofibroblast generation was confirmed by cell treatment with soluble VEGF-A. PRP as single treatment did not induce fibroblast myodifferentiation. This study provides new insights into cellular and molecular mechanisms underpinning PRP antifibrotic action.
Highlights
Platelet-rich plasma (PRP) can be defined as a plasma fraction with platelet concentration higher than the baseline concentration in whole blood
We found that PRP counteracted myofibroblast generation by interfering with the intracellular signaling mediated by transforming growth factor (TGF)-β1, possibly via activation of vascular endothelial growth factor (VEGF)-A/VEGF receptor (VEGFR)-1 mediated signaling
In order to promote fibroblast differentiation towards myofibroblasts, murine NIH/3T3 and human HDFα fibroblastic cells were cultured in differentiation medium (DM) consisting of a low serum medium (DMEM plus 2% fetal bovine serum (FBS)) with the addition of the profibrotic agent TGF-β1 (2 ng/mL)
Summary
Platelet-rich plasma (PRP) can be defined as a plasma fraction with platelet concentration higher than the baseline concentration in whole blood (approximately 1.5 to 8 times physiological platelet counts). Cells 2018, 7, 142 numerous platelet-derived biologically active molecules including growth factors and cytokines, holding a strong potential for improving tissue healing and regeneration [1,2,3,4]. Fibrosis represents a pathological condition frequently occurring as aberrant response to an injury or chronic diseases at multiple organs It presents as an excessive tissue scarring due to an overproduction and deposition of extracellular matrix (ECM) mainly attributable to the imbalance between synthesis and degradation of ECM components, collagens, often in association with uncoordinated detrimental contractures. Some reports show limited effectiveness or inefficacy of this blood-derived product in counteracting the fibrotic response [46,47,48,49], or even a fibrosis development after PRP treatment [35,50,51,52]
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