Abstract
The thymus plays a significant role in establishing immunological self-tolerance. Previous studies have revealed that host immune reaction to allogeneic transplants could be regulated by thymus transplantation. However, physiological thymus involution hinders the clinical application of these insights. Here, we report an efficient generation of thymic epithelial-like tissue derived from induced pluripotent stem cells (iPSCs) and its potential to regulate immune reaction in allogeneic transplantation. We established an iPSC line which constitutively expresses mouse Foxn1 gene and examined the effect of its expression during in vitro differentiation of thymic epithelial cells (TECs). We found that Foxn1 expression enhances the differentiation induction of cells expressing TEC-related cell surface molecules along with upregulation of endogenous Foxn1. iPSC-derived TECs (iPSC-TECs) generated T cells in nude recipient mice after renal subcapsular transplantation. Moreover, iPSC-TEC transplantation to immuno-competent recipients significantly prolonged the survival of allogeneic skin. Our study provides a novel concept for allogeneic transplantation in the setting of regenerative medicine.
Highlights
The thymus plays a significant role in establishing immunological self-tolerance
We first focused on constructing a step-by-step protocol for induction of thymic epithelial cells (TECs) through definitive endoderm (DE), anterior foregut endoderm (AFE), and pharyngeal endoderm (PE) (Fig. 1a)
We have demonstrated that mouse induced pluripotent stem cells (iPSCs), integrated with exogenous Foxn[1] gene, efficiently differentiate into thymic epithelial cells, and transplantation of in vitro generated thymic aggregates induces prolonged survival of transplanted grafts
Summary
The thymus plays a significant role in establishing immunological self-tolerance. Previous studies have revealed that host immune reaction to allogeneic transplants could be regulated by thymus transplantation. To prevent the release of auto-reactive T cells from the thymus, immature T cells encounter thymic antigen presenting cells (APCs), which express a wide spectrum of self-antigen-derived peptides combined with major histocompatibility complex (MHC) molecules. This process allows elimination of auto-reactive T cells and induces regulatory T cells[1]. Thymic lobes transplanted without haematopoietic cells, but containing epithelial structure, tolerizes the host immune system to the thymus donor mouse strain[2,3] These results suggest that intrathymic haematopoietic APCs are not necessary for establishing donor-specific unresponsiveness. Even though it is possible to graft an aged thymus, there would be less ability to tolerize the recipient immune system
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