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

Abstract

SUMMARY 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 T cell development represents a promising approach to reach this goal; however, progress toward generating functional TECs has been limited. Here, we describe a robust in vitro 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 T cell development upon transplantation into thymus-deficient mice. Importantly, the engrafted TEPs produce T cells capable of in vitro proliferation as well as in vivo 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.

Humanized hemato-lymphoid system mice

“…67,68 Recently, it was demonstrated that the transplantation of human embryonic stem cell-derived thymic epithelial progenitors into thymus-deficient nude mice supports the development of functional human T cells. 69 Neither approach, however, is accessible to most investigators due to the limited availability of embryonic and fetal tissues. Moreover, the biology of human thymus educated T cells and their reactivity against the xenogeneic environment needs to be further characterized.…”

T cells in the control of organ-specific autoimmunity

“…Coupled with such regenerative strategies, advances in genetic modification of stem cells and iPSCs may soon allow us to engineer thymus or correct defects in order to modulate and enforce tolerance. Although not ready for prime time, these therapeutic strategies have tremendous potential, considering that human embryonic stem cells have recently been used to generate both thymic epithelial progenitors (196,197) and islet-like structures (198,199) that recapitulate the function of their adult differentiated counterparts upon transplantation in mice or humanized models.…”

Perspectives for Improvement of the Thymic Microenvironment through Manipulation of Thymic Epithelial Cells: A Mini-Review

“…In this way, strategies to manipulate the expression of the critical TEC transcription factor forkhead box n1 (FoxN1) or the activation of TEPCs, recently identified in the adult thymus [47], provide novel strategies to potentially generate more sustained thymus rejuvenation in aging individuals. In addition, protocols have been developed for the directed differentiation of pluripotent stem cells into TEPC in mice and humans [48,49,50,51], for the potential transplantation of de novo generated TEPC. These findings are summarized in table 2 and reviewed below.…”