Petzold Tim, Brivio Sarah, Linnerz Tanja, Watanabe Masakatsu, Gerhardt Holger, Bertrand Julien Y
University of Geneva, Faculty of Medicine, Department of Pathology and Immunology, Rue Michel-Servet 1, Geneva 4, Switzerland.
Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
Biol Open. 2025 Aug 15;14(8). doi: 10.1242/bio.062118. Epub 2025 Aug 12.
Haematopoietic stem and progenitor cells (HSPCs) derive from a subset of endothelial cells (ECs), known as haemogenic ECs by the process of endothelial-to-haematopoietic transition (EHT). Although many factors involved in EHT have been elucidated, we still have a poor understanding of the temporal regulation of this process. Mitochondrial-derived reactive oxygen species (ROS) have been shown to stabilise the hypoxia-inducible factor 1/2α (Hif1/2α) proteins, allowing them to positively regulate EHT. Here, we show a developmental delay in EHT and HSPC induction in a connexin (cx)41.8 (orthologous to mammalian CX40) gap junction mutant, in zebrafish. In mammalian cells, CX40 has been shown to localise to the mitochondria. We demonstrate that Cx41.8 is important for the correct temporal generation of mitochondrial ROS, which stabilise the Hif pathway, allowing for the subsequent specification of the haemogenic endothelium. Taken together, our data indicate that Cx41.8 governs the correct temporal induction of HSPCs.
造血干细胞和祖细胞（HSPCs）源自内皮细胞（ECs）的一个亚群，即通过内皮向造血转化（EHT）过程形成的造血内皮细胞。尽管已经阐明了许多参与EHT的因素，但我们对这一过程的时间调控仍知之甚少。线粒体衍生的活性氧（ROS）已被证明可稳定缺氧诱导因子1/2α（Hif1/2α）蛋白，使其能够正向调节EHT。在这里，我们展示了斑马鱼中连接蛋白（cx）41.8（与哺乳动物CX40同源）间隙连接突变体在EHT和HSPC诱导方面的发育延迟。在哺乳动物细胞中，CX40已被证明定位于线粒体。我们证明Cx41.8对于线粒体ROS的正确时间生成很重要，线粒体ROS可稳定Hif通路，从而允许随后造血内皮细胞的特化。综上所述，我们的数据表明Cx41.8控制着HSPCs的正确时间诱导。
