1、Cell Stem Cell：解析人类巨核细胞的发育过程
2020年12月18日，来自中国医学科学院周家喜、刘兵、石莉红等研究人员合作在《细胞—干细胞》杂志上发表了题为“Decoding Human Megakaryocyte Development.”的研究结果，解析人类巨核细胞的发育过程。
Fig 1 |来源：Cell Stem Cell
通过使用来自卵黄囊（YS）和胎儿肝（FL）的人类早期巨核细胞（MK）单细胞RNA测序，研究人员表征了早期巨核细胞生成的转录组、细胞异质性和发育轨迹。在YS和FL中，研究人员发现异质MK亚群具有独特的发育途径和基因表达模式，可以反映早期的功能分化。有趣的是，研究人员在体内鉴定了一个CD42b+CD14+MK亚群，该亚群显示出免疫反应相关基因的高表达，并且也可以在体外从人类胚胎干细胞（hESC）中产生。此外，研究人员将THBS1鉴定为MK倾向的胚胎内皮细胞早期标记。总体而言，这项研究为解剖早期人类巨核细胞生成的分子和细胞程序提供了重要的见识和宝贵的资源。
据了解，尽管人们对胚胎免疫发育的了解日益加深，但稀有的早期MK仍然研究不足。
英文：
Highlights
1.A comprehensive single-cell transcriptomic landscape of human MKs is constructed
2.MKs show cellular heterogeneity with distinct metabolic and cell cycle signatures
3.CD14 +MKs with immune characteristics are generated along a distinct trajectory
4.THBS1 is identified as an early marker for MK-biased endothelial cells from hESCs
Summary
Despite our growing understanding of embryonic immune development, rare early megakaryocytes (MKs) remain relatively understudied. Here we used single-cell RNA sequencing of human MKs from embryonic yolk sac (YS) and fetal liver (FL) to characterize the transcriptome, cellular heterogeneity, and developmental trajectories of early megakaryopoiesis. In the YS and FL, we found heterogeneous MK subpopulations with distinct developmental routes and patterns of gene expression that could reflect early functional specialization. Intriguingly, we identified a subpopulation of CD42b +CD14 + MKs in vivo that exhibit high expression of genes associated with immune responses and can also be derived from human embryonic stem cells (hESCs) in vitro. Furthermore, we identified THBS1 as an early marker for MK-biased embryonic endothelial cells. Overall, we provide important insights and invaluable resources for dissection of the molecular and cellular programs underlying early human megakaryopoiesis.
（评论：首次在单细胞尺度解析了人胚早期巨核细胞的异质性及发育规律，揭示了巨核细胞在不同胚胎造血位点的特征差异。 同时整合人胚及人胚胎干细胞研究模型，发现巨核细胞的命运决定可能比之前的认知更早。这些发现对于人类巨核细胞发育的理解提供了新的视角，为体外血小板再生策略奠定了理论基础。）
文章来源：
Hongtao Wang, Jian He, Changlu Xu et al, Decoding Human Megakaryocyte Development. DOI: 10.1016/j.stem.2020.11.006. Cell Stem Cell：最新IF：21.464
2、Cell Metabolism：非经典的谷氨酸半胱氨酸连接酶活性可以阻止铁死亡
2020年12月23日，来自美国莫菲特癌症中心Gina M. DeNicola研究团队在《细胞—代谢》上发表了题为“Non-canonical Glutamate-Cysteine Ligase Activity Protects against Ferroptosis.”的研究结果，发现非经典的谷氨酸半胱氨酸连接酶活性可以阻止铁死亡。
Fig 2| Cell Metabolism
半胱氨酸是维持正常细胞和转化细胞中细胞氧化还原稳态所必需的。剥夺半胱氨酸会导致铁依赖的细胞死亡形式，称为铁死亡。研究人员发现，非小细胞肺癌细胞系的胱氨酸饥饿诱导了γ-谷氨酰胺肽的意外积累，这是由于谷氨酸-半胱氨酸连接酶催化亚基（GCLC）的非经典活性而产生的。此活性富集在高水平NRF2（GCLC的关键转录调节因子）的细胞系中，但在半胱氨酸受限后在健康的鼠类组织中也可诱导。
γ-谷氨酰肽的合成限制了谷氨酸的积累，从而防止了铁死亡。这些结果表明，GCLC通过在胱氨酸饥饿下维持谷氨酸稳态而在保护铁死亡中具有与谷胱甘肽无关的非经典作用。
英文：
Highlights
1.Cystine starvation induces γ-glutamyl-peptide accumulation in NSCLC cells
2.GCLC catalyzes γ-glutamyl-peptide synthesis via a GSH-independent mechanism
3.NRF2 protects against ferroptosis via γ-glutamyl-peptide synthesis
4.γ-glutamyl-peptide synthesis prevents ferroptosis by reducing glutamate stress
Summary
Cysteine is required for maintaining cellular redox homeostasis in both normal and transformed cells. Deprivation of cysteine induces the iron-dependent form of cell death known as ferroptosis; however, the metabolic consequences of cysteine starvation beyond impairment of glutathione synthesis are poorly characterized. Here, we find that cystine starvation of non-small-cell lung cancer cell lines induces an unexpected accumulation of γ-glutamyl-peptides, which are produced due to a non-canonical activity of glutamate-cysteine ligase catalytic subunit (GCLC). This activity is enriched in cell lines with high levels of NRF2, a key transcriptional regulator of GCLC, but is also inducible in healthy murine tissues following cysteine limitation. γ-glutamyl-peptide synthesis limits the accumulation of glutamate, thereby protecting against ferroptosis. These results indicate that GCLC has a glutathione-independent, non-canonical role in the protection against ferroptosis by maintaining glutamate homeostasis under cystine starvation.
（评论：半胱氨酸饥饿的代谢后果超出了谷胱甘肽合成受损的影响，其背后的原因目前尚不明确。）
文章来源：
Yun Pyo Kang, Andrea Mockabee-Macias et L, Non-canonical Glutamate-Cysteine Ligase Activity Protects against Ferroptosis. DOI: 10.1016/j.cmet.2020.12.007, Cell Metabolism：最新IF：22.415
3、Cell Metabolism：揭示摄入高果糖的危害
2020年12月22日，来自美国纪念斯隆-凯特琳癌症中心Kayvan R. Keshari和Michael G. Kharas研究团队合作在《细胞-代谢》发表了题为“High Fructose Drives the Serine Synthesis Pathway in Acute Myeloid Leukemic Cells.”的研究结果，发现在急性髓样白血病细胞中高果糖诱导了丝氨酸合成途径的开启。
Fig 3| 来源：Cell Metabolism
研究人员发现白血病细胞的果糖代谢可以通过靶向丝氨酸从头合成途径（SSP）来抑制。不同于高葡萄糖的情况，在富含果糖的情况下，与其对应的正常细胞相比，白血病细胞更加依赖于SSP。该代谢途径由氧化还原辅因子NAD+/ NADH的比率介导，并且增加的SSP通量有利于谷氨酰胺生成α-酮戊二酸，即使在缺乏葡萄糖的情况下，白血病细胞也可以增殖。在高果糖情况下，抑制SSP途径的限速酶PHGDH可以显著减少小鼠白血病的发病率，从而证实了SSP在白血病细胞代谢可塑性中的重要作用。
据了解，显着增加的果糖食用量被认为是癌症的潜在诱导因素。癌细胞利用果糖的代谢适应性为其恶性生长提供了优势，但尚未发现有效的治疗靶点。
英文：
Highlights
1.AML cells proliferate in glucose-deprived environments with fructose supplementation
2.Fructose is mainly metabolized through hexokinase, not ketohexokinase, in AML cells
3.AML cells upregulate the serine synthesis pathway in fructose-rich environments
4.PHGDH inhibition in high-fructose conditions markedly reduces leukemia progression
Summary
A significant increase in dietary fructose consumption has been implicated as a potential driver of cancer. Metabolic adaptation of cancer cells to utilize fructose confers advantages for their malignant growth, but compelling therapeutic targets have not been identified. Here, we show that fructose metabolism of leukemic cells can be inhibited by targeting the de novo serine synthesis pathway (SSP). Leukemic cells, unlike their normal counterparts, become significantly dependent on the SSP in fructose-rich conditions as compared to glucose-rich conditions. This metabolic program is mediated by the ratio of redox cofactors, NAD +/NADH, and the increased SSP flux is beneficial for generating alpha-ketoglutarate from glutamine, which allows leukemic cells to proliferate even in the absence of glucose. Inhibition of PHGDH, a rate-limiting enzyme in the SSP, dramatically reduces leukemia engraftment in mice in the presence of high fructose, confirming the essential role of the SSP in the metabolic plasticity of leukemic cells.
（评论：揭示了果糖促进白血病发生的分子机制，从而解开了骨髓微环境中果糖水平异常升高的谜团。虽尚未发现有效的治疗靶点，或许介导这一代谢重编程的关键酶——PHGDH，或许可以作为一个新的药物靶点用于白血病的治疗。）
文章来源：
Sangmoo Jeong, Angela Maria Savino et al, High Fructose Drives the Serine Synthesis Pathway in Acute Myeloid Leukemic Cells,DOI: 10.1016/j.cmet.2020.12.005, Cell Metabolism：最新IF：22.415
