The miR-212-3p/transferrin axis promotes bone regeneration by modulating iron homeostasis through Schwann cell...

Functional bone regeneration relies on cross talk between nerves and bone, yet the regulatory mechanisms linking Schwann cells (SCs) to osteoporotic bone marrow mesenchymal stem cells (OP-BMSCs) remain unclear. This study demonstrated that SC-Exosomes (Exos) promoted the osteogenic differentiation of OP-BMSCs, and miRNA-mRNA sequencing revealed that SC-Exos, which contained the key mediator miR-212-3p, facilitated osteogenesis by suppressing the ferroptosis pathway in OP-BMSCs. miR-212-3p overexpression combined with transferrin (TF) knockdown or overexpression confirmed that miR-212-3p suppresses TF expression and validated the role of the miR-212-3p/TF axis, which maintained iron homeostasis in BMSCs, alleviated iron overload and oxidative stress, and promoted osteogenic differentiation. Furthermore, an injectable SC-Exos-loaded gelatin methacrylate hydrogel (SC-Exos/GelMA) targeting BMSCs was constructed. In vitro, SC-Exos/GelMA enabled sustained release of Exos and promoted BMSCs osteogenesis. In vivo, SC-Exos/GelMA downregulated TF expression via the miR-212-3p/TF axis, mitigated ferroptosis, restored iron homeostasis, accelerated angiogenesis/neurogenesis, and promoted bone regeneration. This study not only elucidated the role of the miR-212-3p/TF axis in the modulation of BMSCs iron homeostasis, but also constructed an injectable SC-Exos/GelMA hydrogel for bone regeneration, offering mechanistic insights and a translational therapeutic strategy for bone regeneration in clinic.