Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
Dev Cell. 2022 Mar 14;57(5):610-623.e8. doi: 10.1016/j.devcel.2022.02.003. Epub 2022 Feb 24.
Human pluripotent stem cells (hPSCs) can self-renew indefinitely or can be induced to differentiate. We previously showed that exogenous glutamine (Gln) withdrawal biased hPSC differentiation toward ectoderm and away from mesoderm. We revealed that, although all three germ lineages are capable of de novo Gln synthesis, only ectoderm generates sufficient Gln to sustain cell viability and differentiation, and this finding clarifies lineage fate restrictions under Gln withdrawal. Furthermore, we found that Gln acts as a signaling molecule for ectoderm that supersedes lineage-specifying cytokine induction. In contrast, Gln in mesoderm and endoderm is the preferred precursor of α-ketoglutarate without a direct signaling role. Our work raises a question about whether the nutrient environment functions directly in cell differentiation during development. Interestingly, transcriptome analysis of a gastrulation-stage human embryo shows that unique Gln enzyme-encoding gene expression patterns may also distinguish germ lineages in vivo. Together, our study suggests that intracellular Gln may help coordinate differentiation of the three germ layers.
人类多能干细胞（hPSCs）可以无限自我更新或被诱导分化。我们之前曾表明，外源性谷氨酰胺（Gln）耗竭使 hPSC 分化偏向外胚层而远离中胚层。我们揭示了，尽管所有三种生殖谱系都能够从头合成 Gln，但只有外胚层能够产生足够的 Gln 来维持细胞活力和分化，这一发现阐明了 Gln 耗竭下的谱系命运限制。此外，我们发现 Gln 作为外胚层的信号分子，取代了谱系特异性细胞因子的诱导。相比之下，中胚层和内胚层中的 Gln 是α-酮戊二酸的首选前体，而没有直接的信号作用。我们的工作提出了一个问题，即在发育过程中，营养环境是否直接作用于细胞分化。有趣的是，对原肠胚阶段人类胚胎的转录组分析表明，独特的 Gln 酶编码基因表达模式也可能在体内区分生殖谱系。总之，我们的研究表明，细胞内 Gln 可能有助于协调三个胚层的分化。
