TBE56-functionalized thermosensitive hydrogel enhances ferroptosis-associated injury resistance of prominin-2-overexpressing BMSCs for intervertebral disc regeneration

Abstract Our previous studies have confirmed that targeting bone marrow mesenchymal stem cell (BMSC) ferroptosis can enhance the efficiency of stem cell-based repair for degenerated intervertebral discs (IVDs). Our findings indicated that Prominin-2 overexpression is associated with enhanced FBXO22-mediated BACH1 degradation through a p53-associated regulatory mechanism, providing mechanistic insight into its protective role under oxidative stress. Furthermore, treatment with TBE56 on Prominin-2-overexpressing BMSCs further enhances FBXO22-associated regulation of BACH1 and is associated with improved ferroptosis-associated injury resistance of LV-PROM2-overexpressing BMSCs. Therefore, we designed a TBE56-containing hydrogel (TBE56/Gel) to deliver LV-PROM2-overexpressing BMSCs for repairing rat degenerated IVDs. Loading LV-PROM2-overexpressing BMSCs into TBE56/Gel further enhances their resistance to ferroptosis-associated oxidative injury, is associated with treatment-related transcriptomic alterations in BMSCs under oxidative stress, and effectively modulates the oxidative stress microenvironment within degenerated IVDs. Finally, both in vitro Transwell coculture and in vivo experiments validated the therapeutic efficacy of LV-PROM2-loaded BMSCs within TBE56/Gel in repairing degenerated nucleus pulposus cells and IVD tissues. Additionally, TBE56/Gel loading enhances NP-associated regenerative characteristics of LV-PROM2-loaded BMSCs. This study represented an in-depth continuation and expansion of our previous research on targeting BMSC ferroptosis.