Synergistic Effects of Magnesium and Zinc Ions on Neural Stem Cell Proliferation and Differentiation

Regeneration of the central and peripheral nervous system is challenging because of the inherent low regenerative capacity. Transplantation of neural stem cells (NSCs) is a promising strategy to increase regenerative capacity, but limited viability, slow proliferation, and differentiation create significant hurdles. Combining neurostimulator bio-functional ions such as magnesium (Mg²⁺) and zinc (Zn²⁺) to mitigate this limitation could be a breakthrough for future nerve regeneration treatments. This is the first study to investigate the effects of combined Mg²⁺ and Zn²⁺ ion therapy on the proliferation and differentiation of NSCs. The results showed an optimal concentration of Mg²⁺ and Zn²⁺ ions individually improved NSC proliferation, with a synergistic effect observed when ions were combined. The synergistic effect also significantly enhanced neurite outgrowth, promoted advanced neuronal network formation, and increased Nestin, βIII-tubulin, and MAP2 gene expression. These findings highlight the potential of combination therapy of Mg²⁺ and Zn²⁺ ions, which can be used as complementary modulators with NSCs-based treatments, providing promising ion-based therapeutic strategies in neural repair and regenerative medicine.