Generation of Functional Thymic Epithelium from Human Embryonic Stem Cells that Supports Host T Cell Development

Abstract

Inducing immune tolerance to prevent rejection is a key step toward successful engraftment of stem-cell-derived tissue in a clinical setting. Using human pluripotent stem cells to generate thymic epithelial cells (TECs) capable of supporting Tcell development represents a promising approach to reach this goal; however, progress toward generating functional TECs has been limited. Here, we describe a robust invitro method to direct differentiation of human embryonic stem cells (hESCs) into thymic epithelial progenitors (TEPs) by precise regulation of TGFβ, BMP4, RA, Wnt, Shh, and FGF signaling. The hESC-derived TEPs further mature into functional TECs that support Tcell development upon transplantation into thymus-deficient mice. Importantly, the engrafted TEPs produce Tcells capable of invitro proliferation as well as invivo immune responses. Thus, hESC-derived TEP grafts may have broad applications for enhancing engraftment in cell-based therapies as well as restoring age- and stress-related thymic decline.