Allogeneic platelet-rich plasma inhibits ferroptosis in promoting wound repair of type 2 diabetic ulcers

Abstract

Increasing evidence has revealed the emerging role of ferroptosis in the pathophysiology of type 2 diabetes mellitus (T2DM) and its complications. Platelet-rich plasma (PRP) has been demonstrated to facilitate the healing of T2DM ulcers. However, the mechanism by which PRP repairs T2DM ulcers remains unclear. Here, we sought to investigate the interaction between PRP and ferroptosis in repairing T2DM ulcers. The results showed that the cellular activity, proliferation, and migration of fibroblasts were down-regulated, and the cellular activity and normal function of vascular endothelial cells were impaired in the high glucose environment or under RSL3 conditions (a GSH peroxidase 4 inhibitor and ferroptosis inducer). Additionally, both cells experienced over-activation of multiple forms of reactive oxygen species (ROS) and lipid peroxidation. In the T2DM rat model, we observed a decreased rate of ulcer wound healing, impaired proliferative capacity, diminished vascular regeneration, and marked inflammation and hyperfibrosis. More importantly, there was typical damage to mitochondria, increased levels of iron ions, and consistent alterations in protein expression of ferroptosis-related factors. These factors include cyclooxygenase-2 (COX2), glutathione peroxidase 4 (GPX4), transferrin receptor (TFRC), and Solute Carrier Family 7 Member 11 (SLC7A11), among others. Due to the strong association between ferroptosis and T2DM ulcers, the use of allogeneic platelet-rich plasma (Al-PRP) exhibited physiological effects similar to those of the ferroptosis inhibitor Ferrostatin-1 (Fer-1). In vivo experiments, both drugs inhibited a range of impediments to wound healing caused by T2DM and ameliorated the adverse effects associated with ferroptosis. Moreover, Al-PRP attenuated the impairment of normal cellular function, activation of ROS and lipid peroxidation induced by high glucose or RSL3. These results suggested that ferroptosis was involved in the development of T2DM ulcers, which could be treated with Al-PRP by inhibiting ferroptosis, and inhibition of ferroptosis may be a suitable treatment strategy for T2DM ulcers.

Keywords: Allogeneic platelet-rich plasma; Diabetes mellitus; Diabetic ulcer; Ferroptosis; Type 2 diabetes mellitus; Wound healing.