Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
Cell Stem Cell. 2013 Aug 1;13(2):230-6. doi: 10.1016/j.stem.2013.06.014.
Thymus transplantation has great clinical potential for treating immunological disorders, but the shortage of transplant donors limits the progress of this therapy. Human embryonic stem cells (hESCs) are promising cell sources for generating thymic epithelial cells. Here, we report a stepwise protocol to direct the differentiation of hESCs into thymic epithelial progenitor-like cells (TEPLCs) by mimicking thymus organogenesis with sequential regulation of Activin, retinoic acid, BMP, and WNT signals. The hESC-derived TEPLCs expressed the key thymic marker gene FOXN1 and could further develop in vivo into thymic epithelium expressing the functional thymic markers MHC II and AIRE upon transplantation. Moreover, the TEPLC-derived thymic epithelium could support mouse thymopoiesis in T-cell-deficient mice and promote human T cell generation in NOD/SCID mice engrafted with human hematopoietic stem cells (hHSCs). These findings could facilitate hESC-based replacement therapy and provide a valuable in vitro platform for studying human thymus organogenesis and regeneration.
胸腺移植在治疗免疫性疾病方面具有巨大的临床潜力，但移植供体的短缺限制了这种治疗方法的进展。人胚胎干细胞（hESC）是生成胸腺上皮细胞的有前途的细胞来源。在这里，我们通过模拟胸腺器官发生，顺序调节激活素、维甲酸、BMP 和 WNT 信号，报告了一个逐步方案，将 hESC 定向分化为胸腺上皮祖细胞样细胞（TEPLC）。hESC 衍生的 TEPLC 表达关键的胸腺标记基因 FOXN1，并在移植后可进一步在体内发育为表达功能性胸腺标记物 MHC II 和 AIRE 的胸腺上皮。此外，TEPLC 衍生的胸腺上皮可在 T 细胞缺陷小鼠中支持小鼠胸腺生成，并在植入人造血干细胞（hHSCs）的 NOD/SCID 小鼠中促进人 T 细胞生成。这些发现可以促进基于 hESC 的替代治疗，并为研究人类胸腺发生和再生提供有价值的体外平台。
