Evolutionarily Distinctive Transcriptional and Signaling Programs Drive Human Germ Cell Lineage Specification from Pluripotent Stem Cells
Evolutionarily Distinctive Transcriptional and Signaling Programs Drive Human Germ Cell Lineage Specification from Pluripotent Stem Cells
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DOI：
10.1016/j.stem.2017.09.005
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发表时间：
2017-10-05
期刊：
影响因子：
23.9
通讯作者：
Saitou, Mitinori
中科院分区：
文献类型：
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作者：
Kojima, Yoji;Sasaki, Kotaro;Saitou, Mitinori
种系规范是人类生殖和进化的基础，但由于它发生在囊胚植入后不久，因此很难在人类中进行研究。这一过程可以用人类诱导多能干细胞（hiPSCs）模拟，通过早期中胚层样细胞（iMeLC）状态将其分化为原始生殖细胞样细胞（hpgclc）。在这里，我们阐明了驱动hPGCLC从iPSCs分化的关键转录因子及其与重要信号通路的相互作用。iMeLCs的种系能力取决于WNT信号的持续时间和剂量，WNT信号诱导EOMES的表达以激活SOX17， SOX17是hPGCLC规范的关键驱动因素。在hPGCLC诱导下，BMP信号以不依赖于sox17的方式激活TFAP2C。然后，SOX17和TFAP2C共同启动hPGCLC转录程序，包括BLIMP1的表达。该规范程序在关键转录因子及其层次结构方面与小鼠规范程序有所不同，为进一步研究人类生殖细胞发育提供了基础。
Germline specification underlies human reproduction and evolution, but it has proven difficult to study in humans since it occurs shortly after blastocyst implantation. This process can be modeled with human induced pluripotent stem cells (hiPSCs) by differentiating them into primordial germ cell-like cells (hPGCLCs) through an incipient mesoderm-like cell (iMeLC) state. Here, we elucidate the key transcription factors and their interactions with important signaling pathways in driving hPGCLC differentiation from iPSCs. Germline competence of iMeLCs is dictated by the duration and dosage of WNT signaling, which induces expression of EOMES to activate SOX17, a key driver of hPGCLC specification. Upon hPGCLC induction, BMP signaling activates TFAP2C in a SOX17-independent manner. SOX17 and TFAP2C then cooperatively instate an hPGCLC transcriptional program, including BLIMP1 expression. This specification program diverges from its mouse counterpart regarding key transcription factors and their hierarchies, and it provides a foundation for further study of human germ cell development.