Transplantation of MHC-mismatched Mouse Embryonic Stem Cell-Derived Thymic Epithelial Progenitors Prevents Autoimmune Diabetes

Abstract

Abstract Type 1 diabetes (T1D) is an autoimmune disease results from the destruction of insulin-secreting islet β-cells by autoreactive T cells. NOD mice are the widely used animal model for human T1D. Autoimmunity in NOD mice is associated with particular MHC loci and impaired islet autoantigen expression and/or presentation in the thymus, which results in defects in both central and peripheral tolerance. It has been reported that induction of mixed chimerism with MHC-mismatched, but not MHC-matched donor bone marrow (BM) transplants prevents the development T1D in NOD mice. We have reported that mouse embryonic stem cells (mESCs) can be selectively induced in vitro to generate thymic epithelial progenitors (TEPs) that further develop into thymic epithelial cells (TECs) in vivo to support T cell development. We show here that transplantation of MHC-mismatched mESC-TEPs and MHC-matched donor BM prevents insulitis and T1D development in NOD mice. This is associated with higher expression of proinsulin 2, a key islet autoantigen, in the mESC-TECs, and an increased number of regulatory T cells. Our results suggest that embryonic stem cell-derived TEPs may offer a new approach to control T1D.