Cell Death Discovery (Sep 2023)

δ-Tocotrienol preconditioning improves the capability of bone marrow-derived mesenchymal stem cells in promoting wound healing by inhibiting BACH1-related ferroptosis

  • Xiao He,
  • Dawei Wang,
  • Yi Yi,
  • Yufang Tan,
  • Min Wu,
  • Haiping Wang,
  • Weijie Hu,
  • Hongbo Chen,
  • Qi Zhang,
  • Yiping Wu

DOI
https://doi.org/10.1038/s41420-023-01653-1
Journal volume & issue
Vol. 9, no. 1
pp. 1 – 21

Abstract

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Abstract Wound healing is a complex physiological process for maintaining skin integrity after a wound. Bone marrow-derived mesenchymal stem cells (BMSCs) are excellent cellular candidates for wound healing, which could be enhanced by exogenous stimulation. We aimed to explore the role of δ-Tocotrienol (δ-TT) in BMSC ability of wound healing. Firstly, transcriptome and single-cell analysis were used to explore the genes and pathways related to ferroptosis in wound tissues. In vitro, cell proliferation, migration, and angiogenesis of δ-TT-BMSCs were detected. In addition, qRT-PCR and immunofluorescence (IF) were applied for observing the promoting wound healing ability of δ-TT-BMSC conditioned medium (CM) on NIH-3T3 and PAM-212 cells. The level of ferroptosis was determined by the mitochondrial membrane potential and total/lipid reactive oxygen species (ROS) in the cells and the morphological changes of mitochondria were observed by transmission electron microscope. The BTB and CNC homology 1 (BACH1) expression and activation of the PI3K/AKT signaling pathway were detected by IF and western blot (WB). The effect of δ-TT-BMSCs on wound healing was observed in vivo. The regulatory mechanism of δ-TT-BMSCs on ferroptosis was verified by IHC and IF staining. In vitro, δ-TT-BMSCs declined the level of lipid ROS in NIH-3T3 and PAM-212 cells and enhanced mitochondrial membrane potential. In vivo, δ-TT-BMSCs promoted wound healing in mice by decreasing ferroptosis. In terms of mechanism, δ-TT-BMSCs inhibited the expression of BACH1 and activated PI3K/AKT signaling pathway. This study demonstrated the ability of δ-TT-BMSCs to promote wound healing by inhibiting BACH1-related ferroptosis. In addition, PI3K/AKT signaling pathway was activated by δ-TT-BMSCs and could be involved in wound healing. δ-TT-BMSCs might be a promising strategy for treating wounds.