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

Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143-0540, USA.
Cell stem cell (Impact Factor: 22.27). 05/2013; 13(2). DOI: 10.1016/j.stem.2013.04.004
Source: PubMed


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.

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    • "Thymic epithelium was not humanized in our current generation double-chimeric FRGN mice thus limiting its utility for studying human T-cell responses. For this reason it will be desirable to generate tri-chimeric FRGNs in the future, possibly by transplanting iPSC derived human thymic epithelium (Parent et al., 2013) along with the other tissues. "
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    • "Recently, two groups reported methods for the generation of thymic endoderm from human pluripotent stem cells (Parent et al., 2013; Sun et al., 2013). Importantly , these studies showed that differentiated mixed cultures containing thymic progenitors could mature in vivo to form grafts capable of supporting T cell development in nude (Foxn1 À/À ) or other immunocompromised mice. "
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    ABSTRACT: Thymic epithelial cells (TECs) play a critical role in T cell maturation and tolerance induction. The generation of TECs from in vitro differentiation of human pluripotent stem cells (PSCs) provides a platform on which to study the mechanisms of this interaction and has implications for immune reconstitution. To facilitate analysis of PSC-derived TECs, we generated hESC reporter lines in which sequences encoding GFP were targeted to FOXN1, a gene required for TEC development. Using this FOXN1 (GFP/w) line as a readout, we developed a reproducible protocol for generating FOXN1-GFP(+) thymic endoderm cells. Transcriptional profiling and flow cytometry identified integrin-β4 (ITGB4, CD104) and HLA-DR as markers that could be used in combination with EpCAM to selectively purify FOXN1(+) TEC progenitors from differentiating cultures of unmanipulated PSCs. Human FOXN1(+) TEC progenitors generated from PSCs facilitate the study of thymus biology and are a valuable resource for future applications in regenerative medicine.
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