A number of different research groups are working on ways to restore function of the thymus in old individuals, with methods ranging from the introduction of cells with youthful characteristics to the engineering of thymus tissue for transplantation. Promising results have been produced in mice. The thymus is where the immune cells known as T cells mature, and it atrophies fairly early in adult life, reducing the supply of new immune cells to a trickle. That the supply of new cells is so small across most of the life span is one of the factors contributing to the age-related decline of the immune system, and so opening the floodgates to a much larger supply should help to diminish and reverse some of the characteristic failures of an old immune system. Dysfunction of the immune response is a considerable portion of age-related frailty, and it isn't just a matter of failure to deal with invading pathogens. The immune system is also responsible for destroying damaged and potentially threatening cells, such as senescent cells and cancerous cells, and failing that task has equally serious consequences.
The thymus is mainly composed of two types of epithelial cells, medullary thymic epithelial cells and cortex thymic epithelial cells (mTECs and cTECs). The tissue structure and mechanism for T cell development are complicated, with generation of the thymus regulated by complex molecular and cellular interactions of the thymic microenvironment during embryogenesis. Since the development of organ regeneration techniques became available, complete in vitro regeneration of the thymus has been attempted. Steric induction systems are thought to be optimal for tissue regeneration, but three-dimensional (3-D) induction of TECs from induced pluripotent stem cells (iPSCs) has not yet been reported.
Here, we demonstrate the induction of functional TECs from iPSCs by a 3-D spheroid culture system with recruitment of robust numbers of T cells into the peripheral blood. Purified iPSC-derived TECs showed a sufficient expression level of FoxN1 comparable to TECs, and phenotypic analysis revealed that iPSC-derived TECs were expressing K5. Moreover, transplants of cell aggregations into recipient mice were not rejected and there was normal support of T cell development. Functional analysis revealed that T cells showed immune tolerance to both donor and recipient major histocompatibility complexes and could reject an allogeneic third party's skin graft without tumorigenesis. Taken together, these findings raised the possibility of using iPSC-derived TECs induced by 3-D spheroid culture in future regenerative therapy for patients with immunodeficiency.