Endothelial Cell-Selective Adhesion Molecule Expression in Hematopoietic Stem/Progenitor Cells Is Essential for Erythropoiesis Recovery after Bone Marrow Injury

PLOS ONE, Dec 2019

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.

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Endothelial Cell-Selective Adhesion Molecule Expression in Hematopoietic Stem/Progenitor Cells Is Essential for Erythropoiesis Recovery after Bone Marrow Injury

April Endothelial Cell-Selective Adhesion Molecule Expression in Hematopoietic Stem/Progenitor Cells Is Essential for Erythropoiesis Recovery after Bone Marrow Injury Takao Sudo 0 1 Takafumi Yokota 0 1 Daisuke Okuzaki 1 Tomoaki Ueda 0 1 Michiko Ichii 0 1 Tomohiko Ishibashi 0 1 Tomomi Isono 0 1 Yoko Habuchi 0 1 Kenji Oritani 0 1 Yuzuru Kanakura 0 1 0 Department of Hematology and Oncology, Osaka University Graduate School of Medicine , Suita, Osaka , Japan , 2 DNA Chip Development Center, Research Institute for Microbial Diseases, Osaka University , Suita, Osaka , Japan 1 Editor: Connie J Eaves, B.C. Cancer Agency , CANADA 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 anticancer 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-FUtreated 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. - OPEN ACCESS Data Availability Statement: Access to microarray data concerning this study can be found under GEO experiment accession number (GSE 73496). Other data are within the paper and its Supporting Information files. Funding: This work was supported by Grants-in-Aid for Scientific Research (JSPS KAKENHI) Grant Number 25461416. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Introduction Numerous hematopoietic cells are perpetually generated from hematopoietic stem/progenitor cells that exist primarily in the bone marrow (BM) after birth. Among the various types of hematopoietic cells, red blood cells are indispensable to maintain our day-to-day activities throughout life. Indeed, 2–3 million erythrocytes are produced each second in the adult human. An increase in erythropoiesis is required in times of stress, particularly after receiving chemo-radio therapy for cancer treatment. It is not hematopoietic stem cells (HSCs) or multi-potent hematopoietic progenitor cells (HPCs), but erythroid-specific highly proliferative progenitors, that are thought to play critical roles in supporting the large daily output of red blood cells. Progenitors at the burst forming unit-erythrocyte (BFU-E) level are likely to constitute immature erythroid-restricted progenitors, which possess considerable proliferation potential [ 1 ]. These progenitors progressively differentiate into erythroblasts and reticulocytes to produce a tremendous number of mature erythrocytes. Additionally, macrophages appear to play important roles during differentiation. A structural unit called the erythroblastic island, which consists of a central macrophage surrounded by erythroid progenitors at various differentiation stages, can be found in the fetal liver and the BM [ 2 ]. Furthermore, Chow et al. have recently shown that CD169+ macrophages promote erythroid maturation under both homeostatic and stress conditions by acting like a “niche” for erythroblasts [ 3 ]. Accumulating evidence has indicat (...truncated)


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Takao Sudo, Takafumi Yokota, Daisuke Okuzaki, Tomoaki Ueda, Michiko Ichii, Tomohiko Ishibashi, Tomomi Isono, Yoko Habuchi, Kenji Oritani, Yuzuru Kanakura. Endothelial Cell-Selective Adhesion Molecule Expression in Hematopoietic Stem/Progenitor Cells Is Essential for Erythropoiesis Recovery after Bone Marrow Injury, PLOS ONE, 2016, Volume 11, Issue 4, DOI: 10.1371/journal.pone.0154189