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Prominin-2/FBXO22/BACH1 axis protects bone marrow mesenchymal stem cells against TBHP-induced ferroptosis and
Yuzhu Xu1, Lele Zhang2, Mingliang Ji3
1Department of Spine Center, Orthopedics Department, Medical School, Zhongda Hospital, Southeast University, No. 87 DingJiaQiao, GuLou District, Nanjing, 210009, Jiangsu, China. Dr.XuYuzhu@gmail.com.
Background:
Our preliminary research has revealed that Prominin-2 overexpression effectively guarded against oxidative stress (OS)-induced ferroptosis by decreasing BTB and CNC homolog 1 (BACH1) expression, thus promoting bone marrow mesenchymal stem cells (BMSCs) survival under the OS microenvironments in degenerative discs.
Methods:
In this study, we probed how Prominin-2 controls the BACH1 expression in OS-induced BMSC ferroptosis. We then evaluated the efficiency of targeted Prominin-2/BACH1 pathway in BMSCs in treating degenerative nucleus pulposus cells (NPCs) and intervertebral disc degeneration (IVDD).
Results:
Using lentivirus infection and Western Blot, we observed that F-box only protein 22 (FBXO22) levels decreased in OS-induced BMSCs while overexpressing Prominin-2 restored its expression and pharmacological inhibition of FBXO22 impaired Prominin-2-mediated BACH1 degradation. The pull-down assay further confirmed the essential role of FBXO22 in the degradation of BACH1 promoted by Prominin-2. FBXO22 overexpression suppressed BMSCs' ferroptosis, and FBXO22 activity enhancer TBE56 (biotinylated TBE31) could further improve Prominin-2-overexpressed BMSCs' viability under OS circumstances. Finally, in vitro co-culture and in vivo studies illustrated that engraftment of Prominin-2-overexpressed BMSCs pre-treated by TBE56 enhanced the treatment efficiency of BMSCs for degenerative NPCs and rats' IVDD.
Conclusions:
Our data proposed a novel treatment strategy targeting the ferroptosis of BMSCs for treating IVDD by regulating FBXO22 in Prominin-2-overexpressed BMSCs.
