Endothelial Cell-Selective Adhesion Molecule Contributes to the Development of Definitive Hematopoiesis in the Fetal Liver

Summary: 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. : Ueda et al. shed light on the contribution of endothelial cell-selective adhesion molecule (ESAM) to the ontogeny of definitive hematopoiesis. ESAM deficiency caused high mortality in fetuses after mid-gestation. Expression of Alas2 and adult-type globin genes decreased in ESAM-null HSCs, which resulted in the impairment of development of adult-type erythropoiesis. The authors also revealed functional involvement of ESAM-expressing endothelial cells. Keywords: definitive hematopoiesis, endothelial cell-selective adhesion molecule, hematopoietic stem cells, endothelial cells, fetal liver