De novo Thymus Reconstitution: The Rising of Cell-based Strategies

The thymus plays a crucial role in the generation of functional T cells, which are essential in adaptive immune responses. However, the involution, dysfunction, and even absence of the thymus induced by various factors such as aging, heredity, tumor, infection, and surgical removal, greatly impair or completely deprive the normal functions of the thymus and has been threatening the health of countless patients. Thus, reconstituting the thymus in these patients is remarkably necessary and urgent, in which thymus transplantation is viable, but the rare donors and related complications dramatically limit its clinical application. Other exogenous regeneration therapies, like sex steroid inhibition and cytokines treatments, usually have nonspecific, limited, and transient outcomes. By comparison, de novo cell-based strategies to reconstitute the thymus may be more feasible, which can generate fully functional thymuses usually using autologous cells without the dependence on limited thymus donors, thus avoiding transplant donor shortage as well as related complications, and overcome the defects of exogenous regeneration therapies. In this review, we summarized the progression in this field, including the generation of functional thymic epithelial cells (TECs), the clonogenic culture of TECs, stem cell treatment, and the construction of thymic organoids, to provide a global perspective for cell-based de novo thymus reconstitution.