Endothelial Cell-Selective Adhesion Molecule Expression in Hematopoietic Stem/Progenitor Cells Is Essential for Erythropoiesis Recovery after Bone Marrow Injury.
Endothelial Cell-Selective Adhesion Molecule Expression in Hematopoietic Stem/Progenitor Cells Is Essential for Erythropoiesis Recovery after Bone Marrow Injury.
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DOI：
10.1371/journal.pone.0154189
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Kanakura Y
中科院分区：
文献类型：
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作者：
Sudo T;Yokota T;Okuzaki D;Ueda T;Ichii M;Ishibashi T;Isono T;Habuchi Y;Oritani K;Kanakura Y
在体内平衡状态下，每秒都有大量的红血球从增殖的祖细胞中产生。化疗和放射治疗导致骨髓抑制后，需要增加红细胞生成活性。我们先前的研究表明，内皮细胞选择性黏附分子(ESAM)是一种真正的造血干细胞标记物，在应激诱导的造血中起着至关重要的作用。为了确定ESAM在红系恢复中的生理意义，用抗癌药物5-氟尿嘧啶(5-FU)对ESAM基因敲除(KO)小鼠进行治疗。与野生型(WT)小鼠相比，ESAM-KO小鼠在5-FU治疗后经历了严重和长期的贫血。注射5-FU 8天后，与WT小鼠相比，ESAM-KO小鼠骨髓和脾中的红系祖细胞数量减少，外周血中网织红细胞数量减少。经5-FU处理的ESAM-KO小鼠骨髓巨核细胞-红系祖细胞(MEP)的爆裂形成单位(BFU-E)能力低于WT小鼠。骨髓移植显示，在WT宿主小鼠中，来自ESAM-KO供者的造血干/祖细胞对5-FU的治疗比来自WT供者的造血干/祖细胞更敏感。然而，来自WT供者的造血细胞移植到ESAM-KO宿主小鼠后，正常情况下可以重建骨髓损伤后的红系。这些结果表明，ESAM在造血细胞中的表达，而不是在环境细胞中的表达，是造血恢复的关键。我们还发现，在动态平衡条件下，5-FU可诱导原始红系祖细胞和不表达ESAM的巨噬细胞上调ESAM。巨噬细胞的表型变化可能与应激诱导的急性红细胞生成过程中红系祖细胞与其生态位成分之间的相互作用有关。对5-FU处理的WT和ESAM-KO小鼠原始红系祖细胞的基因芯片分析显示，ESAM-KO小鼠中包括GATA1系统在内的各种信号通路受到损害。因此，我们的数据表明，ESAM在造血祖细胞中的表达是骨髓损伤后红系恢复所必需的。
Numerous red blood cells are generated every second from proliferative progenitor cells under a homeostatic state. Increased erythropoietic activity is required after myelo-suppression as a result of chemo-radio therapies. Our previous study revealed that the endothelial cell-selective adhesion molecule (ESAM), an authentic hematopoietic stem cell marker, plays essential roles in stress-induced hematopoiesis. To determine the physiological importance of ESAM in erythroid recovery, ESAM-knockout (KO) mice were treated with the anti-cancer drug, 5-fluorouracil (5-FU). ESAM-KO mice experienced severe and prolonged anemia after 5-FU treatment compared to wild-type (WT) mice. Eight days after the 5-FU injection, compared to WT mice, ESAM-KO mice showed reduced numbers of erythroid progenitors in bone marrow (BM) and spleen, and reticulocytes in peripheral blood. Megakaryocyte-erythrocyte progenitors (MEPs) from the BM of 5-FU-treated ESAM-KO mice showed reduced burst forming unit-erythrocyte (BFU-E) capacities than those from WT mice. BM transplantation revealed that hematopoietic stem/progenitor cells from ESAM-KO donors were more sensitive to 5-FU treatment than that from WT donors in the WT host mice. However, hematopoietic cells from WT donors transplanted into ESAM-KO host mice could normally reconstitute the erythroid lineage after a BM injury. These results suggested that ESAM expression in hematopoietic cells, but not environmental cells, is critical for hematopoietic recovery. We also found that 5-FU treatment induces the up-regulation of ESAM in primitive erythroid progenitors and macrophages that do not express ESAM under homeostatic conditions. The phenotypic change seen in macrophages might be functionally involved in the interaction between erythroid progenitors and their niche components during stress-induced acute erythropoiesis. Microarray analyses of primitive erythroid progenitors from 5-FU-treated WT and ESAM-KO mice revealed that various signaling pathways, including the GATA1 system, were impaired in ESAM-KO mice. Thus, our data demonstrate that ESAM expression in hematopoietic progenitors is essential for erythroid recovery after a BM injury.