Enhanced Platelet-Rich Plasma (ePRP) Stimulates Wound Healing through Effects on Metabolic Reprogramming in Fibroblasts

Abstract

As a source of growth factors for expediting wound healing and tissue regeneration, plasma-rich plasma (PRP) has been extensively applied in diverse fields including orthopaedics, ophthalmology, oral and maxillofacial surgery, dentistry, and gynaecology. However, the function of PRP in metabolic regulations remains enigmatic. A standardized method was devised herein to enrich growth factors and to lyophilize it as enhanced PRP (ePRP) powder, which could become ubiquitously available without mechanical centrifugation in clinical practice. To identify metabolic reprogramming in human dermal fibroblasts under ePRP treatment, putative metabolic targets were identified by transcriptome profiling and validated for their metabolic effects and mechanism. ePRP does not only promote wound healing but re-aligns energy metabolism by shifting to glycolysis through stimulation of glycolytic enzyme activity in fibroblasts. On the contrary, oxygen consumption rates and several mitochondrial respiration activities were attenuated in ePRP-treated fibroblasts. Furthermore, ePRP treatment drives the mitochondrial resetting by hindering the mitochondrial biogenesis-related genes and results in a dampened mitochondrial mass. Antioxidant production was further increased by ePRP treatment to prevent reactive oxygen species formation. Besides, ePRP also halts the senescence progression of fibroblasts by activating SIRT1 expression. Importantly, the glycolytic inhibitor 2-DG can completely reverse the ePRP-enhanced wound healing capacity, whereas the mitochondrial inhibitor oligomycin cannot. This is the first study to utilize PRP for comprehensively investigating its effects on the metabolic reprogramming of fibroblasts. These findings indicate that PRP’s primary metabolic regulation is to promote metabolic reprogramming toward glycolytic energy metabolism in fibroblasts, preserving redox equilibrium and allowing anabolic pathways necessary for the healing and anti-ageing process.

The Efficiency and Safety of Platelet-Rich Plasma Dressing in the Treatment of Chronic Wounds: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

“…These cells and factors can contribute to regulating epithelial cell proliferation and migration, regulating fibroblastic activity [ 18 ], promoting angiogenesis and vessel permeability [ 53 ], and increasing protein and extracellular matrix synthesis [ 54 ]. In vivo, these growth factors could enhance the metabolic reprogramming of fibroblasts, especially promoting their glycolytic energy metabolism, to stimulate fibroblast proliferation and differentiation during tissue repairing [ 55 ]. Additionally, concentrated platelets could stimulate the proliferation and pro-angiogenic properties of mesenchymal stem cells even under oxidative stress to promote angiogenesis and metabolic support around the wound [ 56 ].…”

Epigenetics, ovarian cell plasticity, and platelet-rich plasma: Mechanistic theories

“…For human luteinized granulosa cells, potassium and sodium channels are homologous with those in neuroendocrine cells of adrenal and thyroid C cells ( Klugbauer et al 1995 , Bulling et al 1999 ). How these ion gates change within ovaries during aging is being studied, but manipulation of cell cycle regulators via redox inputs and voltage gradients has been shown to influence rejuvenation elsewhere ( Durant et al 2017 , Weng et al 2021 , Bakalova et al 2022 ).…”

Hormesis mediates platelet‐rich plasma and wound healing

“…Effects of platelet‐rich plasma (PRP) (enhanced PRP powder) on proliferation in fibroblasts (CCK‐8 assay) (modified from: Weng et al 39 )…”

“…In order to assess the dose response features of the PRP treatment during the wound healing process, it is desirable to have robust study designs with an adequate number of the doses/concentrations tested above and below the biological threshold. In the process of assessing The cell types which have displayed hormetic dose responses induced by PRP have involved a broad spectrum of fibroblast cells (e.g., dermal) (Figures 2-5), [33][34][35][36] oral fibroblasts (Figure 6), 37 ACL fibroblasts (Figure 7), 38 various fibroblast cell lines (Figure 8), 39 keratinocytes (Figures 4, 9), 35,40,41 endothelial cells (e.g., brain, heart, umbilical cord) (Figures 10-12), [42][43][44] bone (e.g. osteoblasts) (Figures 6, 13) 37,45 alveolar bone-part of maxilla and mandible) (Figures 6, 14), 37,46 muscle cells (e.g., C2Cl2) (Figure 15), 47 periodontal ligaments (Figures 16-19), [48][49][50][51] Schwann cells (Figure 20), 52 mesenchymal stem cells (MSCs) (Figure 21), 35,53 and dental/apical papilla stem cells (Figures 22 and 23).…”

“…Effects of platelet-rich plasma (PRP) (enhanced PRP powder) on proliferation in fibroblasts (CCK-8 assay) (modified from: Weng et al 39 ) F I G U R E 9 Effects of platelet lysate (PLS) on matrixmetalloproteinase-9 (MMP-9) activity in HaCaT cells after 24 h exposure (modified from: Ranzato et al 40 ) and collagen synthesis (Table 1). While the above hormetic responses concerned the effects of PRP on various cellular systems, Zhang et al 56 reported that exposure of mouse platelets to near infrared low-level light enhanced ATP production (Figure 24) in an hormetic fashion, extending the storage half-life from 5 to 7 days.…”