FG-4592 Accelerates Cutaneous Wound Healing by Epidermal Stem Cell Activation via HIF-1α Stabilization

Abstract

Background/Aims: Regional hypoxia promptly develops after trauma because of microvascular injury and increased oxygen consumption. This acute hypoxia plays a positive role in early skin wound healing. One of the mechanisms underlying the beneficial effects of acute hypoxia on wound healing may be increased hypoxia-inducible factor-1 (HIF-1α) expression. HIF-1α may affect the wound-healing process through many aspects, including angiogenesis, metabolism, and extra-cellular matrix synthesis and remodelling. Epidermal stem cells (EpSCs) are important participants in wound repair; however, whether these cells are regulated by hypoxia is unclear. This study aimed to elucidate the regulatory mechanism by which hypoxia acts on EpSCs. Methods: CCK8 assays, western blots and live cell station observation were employed to compare the viability, proliferation and motility of EpSCs cultured under normoxic conditions (21% O₂) with those cultured under hypoxic conditions (2% O₂). Moreover, we used FG-4592 (a prolyl hydroxylase inhibitor that stabilizes HIF-1α in normoxia), KC7F2 (a selective inhibitor of HIF-1α transcription) and siRNA against HIF-1α to regulate HIF-1α expression. Results: Acute hypoxia caused EpSCs to switch from a quiescent state to an activated state with higher viability and motility, as well as an earlier proliferation peak. We demonstrated that the HIF-1 signalling pathway mediated hypoxia-induced activation of EpSCs. Finally, the in vivo experiments showed that exogenous FG-4592 effectively accelerates wound healing, shortens healing times and even induces epidermal hyperplasia. Conclusion: This study demonstrated that both hypoxia and exogenous FG-4592 improve EpSC proliferation and motility by stabilizing HIF-1α, and its results suggest that HIF-1α is an important target through which wound healing can be accelerated and that FG-4592 is a promising new drug for wound repair.

Roxadustat promotes angiogenesis through HIF‐1α/VEGF/VEGFR2 signaling and accelerates cutaneous wound healing in diabetic rats

“…Second, because it is already under phase 3 clinical trials, the potential of roxadustat for the treatment of diabetic wounds in humans could be investigated relatively quickly. Third, in addition to its proangiogenetic effect, as indicated in the present study, roxadustat was reported to improve epidermal stem cell proliferation and motility, which could accelerate the re‐epithelialization of keratinocytes to promote cutaneous wound healing. Thus, roxadustat may be a promising candidate for clinical trials for the treatment of diabetic foot ulcers.…”

Von Hippel-Lindau (VHL) Protein Antagonist VH298 Improves Wound Healing in Streptozotocin-Induced Hyperglycaemic Rats by Activating Hypoxia-Inducible Factor- (HIF-) 1 Signalling

“…And Ruthenborg et al first systematically discussed the potential for the use of PHD inhibitors to treat tissue injuries and wounds [17]. Numerous studies demonstrated that PHD-targeted treatment, such as using DMOG or designed compounds, e.g., FG-4592, had satisfactory outcomes in wound healing via the HIF-1 signalling pathway [8, 18–22]. However, the upregulated HIF-1 via VHL inhibition remained largely unknown.…”

Prolyl hydroxylase domain 2 reduction enhances skeletal muscle tissue regeneration after soft tissue trauma in mice

“…This effect is not limited to either macrophages or muscle cells but might involve all cells with reduced Phd2 activity. In view of the upcoming production of pharmacologic PHD inhibitors, application of PHD inhibitors may turn out to be advantageous after skeletal muscle trauma to accelerate regeneration [64,65].…”