Endothelial cell-selective adhesion molecule (ESAM) is a lifelong marker of hematopoietic stem cells (HSCs). Although we previously elucidated the functional importance of ESAM in HSCs in stress-induced hematopoiesis in adults, it is unclear how ESAM affects hematopoietic development during fetal life. To address this issue, we analyzed fetuses from conventional or conditional ESAM-knockout mice. Approximately half of ESAM-null fetuses died after mid-gestation due to anemia. RNA sequencing analyses revealed downregulation of adult-type globins and Alas2, a heme biosynthesis enzyme, in ESAM-null fetal livers. These abnormalities were attributed to malfunction of ESAM-null HSCs, which was demonstrated in culture and transplantation experiments. Although crosslinking ESAM directly influenced gene transcription in HSCs, observations in conditional ESAM-knockout fetuses revealed the critical involvement of ESAM expressed in endothelial cells in fetal lethality. Thus, we showed that ESAM had important roles in developing definitive hematopoiesis. Furthermore, we unveiled the importance of endothelial ESAM in this process.

内皮细胞选择性粘附分子（ESAM）是造血干细胞（HSC）的终身标记。尽管我们先前已经阐明了ESAM在HSC中在成人压力诱导的造血中的功能重要性，但目前尚不清楚ESAM如何影响胎儿生命中的造血发育。为了解决这个问题，我们分析了常规或条件性ESAM基因敲除小鼠的胎儿。约有一半的ESAM无效胎儿在妊娠中期死于贫血。RNA测序分析显示，在ESAM无效的胎儿肝脏中，成人型球蛋白和血红素生物合成酶Alas2的表达下调。这些异常归因于ESAM空HSC的功能失常，这在培养和移植实验中得到了证实。尽管交联ESAM直接影响HSC中的基因转录，对有条件的ESAM基因敲除胎儿的观察表明，ESAM在内皮细胞中表达与胎儿致死性的关键相关。因此，我们证明了ESAM在确定性造血过程中起着重要作用。此外，我们揭示了内皮ESAM在此过程中的重要性。