Endothelial Cell-Selective Adhesion Molecule Contributes to the Development of Definitive Hematopoiesis in the Fetal Liver
Endothelial Cell-Selective Adhesion Molecule Contributes to the Development of Definitive Hematopoiesis in the Fetal Liver
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DOI：
10.1016/j.stemcr.2019.11.002
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发表时间：
2019-11
影响因子：
5.9
通讯作者：
T. Ueda;T. Yokota;D. Okuzaki;Y. Uno;T. Mashimo;Y. Kubota;T. Sudo;Tomohiko Ishibashi;Y. Shingai-Y.-Shinga
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文献类型：
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作者：
T. Ueda;T. Yokota;D. Okuzaki;Y. Uno;T. Mashimo;Y. Kubota;T. Sudo;Tomohiko Ishibashi;Y. Shingai-Y.-Shinga
内皮细胞选择性黏附分子(ESAM)是造血干细胞(HSCs)的终生标志物。虽然我们先前阐明了ESAM在HSCs应激诱导的成人造血中的功能重要性，但目前还不清楚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基因敲除小鼠的胚胎。大约一半的ESAM缺失型胎儿在怀孕中期后死于贫血。RNA测序分析显示，在ESAM缺失的胎儿肝脏中，成人型珠蛋白和Alas2下调，Alas2是一种血红素生物合成酶。这些异常归因于ESAM缺失的HSCs的功能障碍，这在培养和移植实验中得到了证实。虽然交联型ESAM直接影响HSCs的基因转录，但在条件性ESAM基因敲除胎儿中的观察显示，ESAM在胎儿死亡中的关键作用是内皮细胞表达的ESAM。因此，我们表明ESAM在最终的造血发展中具有重要的作用。此外，我们还揭示了内皮ESAM在这一过程中的重要性。
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.