T-cells Derived from Human Embryonic Stem Cells May Prevent Graft Rejection

A recent paper described the development of a method for using human embryonic stem cells (hESCs) to generate fully functional thymus tissue capable of supporting T-cell development and proliferation.

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.

Investigators at the University of California, San Francisco (USA) developed a new method for directing differentiation of hESCs into thymic epithelial progenitors (TEPs), cells that mature into TECs. The in vitro method was based on the precise chronological regulation of several signaling factors including TGF-beta (transforming growth factor-beta), BMP4 (bone morphogenetic protein 4), Wnt (wingless-type MMTV integration site family), Shh (sonic hedgehog), and FGF (fibroblast growth factor).

Timing the activation of these signaling factors was critical. "If we used one factor for a day longer or shorter it would not work," said senior author Dr. Matthias Hebrok, professor of diabetes research at the University of California, San Francisco. "It would be like driving down the highway and missing your exit."

Results published in the May 16, 2013, online edition of the journal Cell Stem Cell revealed that the hESC-derived TEPs matured into functional TECs that supported T-cell development upon transplantation into thymus-deficient mice. Furthermore, the engrafted TEPs produced T-cells capable of in vitro proliferation as well as in vivo immune responses.

"The thymus is an environment in which T-cells mature, and where they also are instructed on the difference between self and nonself," said contributing author Dr. Mark Anderson, professor of medicine at the University of California, San Francisco. "Some T cells are prepared by the thymus to attack foreign invaders—including transplants, while T cells that would attack our own tissues normally are eliminated in the thymus."

The protocol described in this study prompted only about 15% of hESCs to differentiate into functional thymus tissue. Even so, Dr. Anderson said, "We now have developed a tool that allows us to modulate the immune system in a manner that we never had before."

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