Zinc Treatment Stimulates Thymic Regeneration After Bone Marrow Transplant

Prolonged T cell reconstitution after allogeneic hematopoietic stem cell transplant (allo-HSCT) is an important contributor to transplant-related morbidity and mortality due to infection and malignant relapse. Therefore, strategies to enhance thymic reconstitution in allo-HSCT recipients are clinically desirable, although currently limited. Zinc, the second most abundant trace metal in the body, plays an important role in T cell homeostasis and thymic function. In a mouse model of allo-HSCT (Fig. a), we demonstrated that zinc supplementation can significantly improve thymic regeneration (Fig. b). Importantly, these findings in thymus were translated to the periphery as mice that received zinc supplementation showed increased numbers of naïve T cells as well as increased recent thymic emigrants (demonstrated using RAG2-GFP BM donors) model (Fig. c-d) 5-8 weeks after allo-HSCT. We have previously demonstrated that endothelial cells (EC), which are extremely resistant to damage, can promote endogenous thymic regeneration after acute injury via their production of BMP4, a growth factor that targets thymic epithelial cells (TECs), a key population crucial for T cell development. Interestingly, when stimulated in vitro for 24 hours with zinc sulphate, ECs could be directly induced to produce BMP4, but not when exposed to increased zinc import with the cell-permeable zinc pyrithione (Fig. e).