Laboratory of Biochemistry and Cell Biology (URBC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur (UNamur), Namur, Belgium, Namur, Belgium.
Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, United States.
Elife. 2023 Jul 10;12:e78546. doi: 10.7554/eLife.78546.
Using embryonic stem cells (ESCs) in regenerative medicine or in disease modeling requires a complete understanding of these cells. Two main distinct developmental states of ESCs have been stabilized in vitro, a naïve pre-implantation stage and a primed post-implantation stage. Based on two recently published CRISPR-Cas9 knockout functional screens, we show here that the exit of the naïve state is impaired upon heme biosynthesis pathway blockade, linked in mESCs to the incapacity to activate MAPK- and TGFβ-dependent signaling pathways after succinate accumulation. In addition, heme synthesis inhibition promotes the acquisition of 2 cell-like cells in a heme-independent manner caused by a mitochondrial succinate accumulation and leakage out of the cell. We further demonstrate that extracellular succinate acts as a paracrine/autocrine signal, able to trigger the 2C-like reprogramming through the activation of its plasma membrane receptor, SUCNR1. Overall, this study unveils a new mechanism underlying the maintenance of pluripotency under the control of heme synthesis.
使用胚胎干细胞（ESCs）进行再生医学或疾病建模需要对这些细胞有一个完整的了解。ESCs 的两种主要不同的发育状态已经在体外稳定下来，一种是原始的植入前阶段，另一种是原始的植入后阶段。基于最近发表的两项 CRISPR-Cas9 敲除功能筛选，我们在这里表明，血红素生物合成途径阻断会损害原始状态的退出，这与 mESCs 中在琥珀酸积累后无法激活 MAPK 和 TGFβ 依赖的信号通路有关。此外，血红素合成抑制以血红素独立的方式促进 2 种类似细胞的获得，这是由于线粒体琥珀酸积累和细胞内漏出引起的。我们进一步证明，细胞外琥珀酸作为旁分泌/自分泌信号，能够通过其质膜受体 SUCNR1 的激活，触发 2C 样重编程。总的来说，这项研究揭示了血红素合成控制下维持多能性的一个新机制。
