Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143-0540, USA.
Cell Stem Cell. 2013 Aug 1;13(2):219-29. doi: 10.1016/j.stem.2013.04.004. Epub 2013 May 16.
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.
诱导免疫耐受以防止排斥反应是成功将干细胞衍生组织移植到临床环境中的关键步骤。使用人类多能干细胞生成能够支持 T 细胞发育的胸腺上皮细胞 (TEC) 代表了实现这一目标的有前途的方法; 然而，生成功能性 TEC 的进展受到限制。在这里，我们描述了一种强大的体外方法，通过精确调节 TGFβ、BMP4、RA、Wnt、Shh 和 FGF 信号来指导人胚胎干细胞 (hESC) 分化为胸腺上皮祖细胞 (TEP)。hESC 衍生的 TEP 进一步成熟为功能性 TEC，在移植到胸腺缺陷小鼠后支持 T 细胞发育。重要的是，植入的 TEP 产生能够在体外增殖以及体内免疫反应的 T 细胞。因此，hESC 衍生的 TEP 移植物可广泛应用于增强细胞治疗中的植入以及恢复与年龄和应激相关的胸腺衰退。
