Endothelial Cell-Selective Adhesion Molecule Expression in Hematopoietic Stem/Progenitor Cells Is Essential for Erythropoiesis Recovery after Bone Marrow Injury.
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.
Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Takao
T
Sudo
Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Takafumi
T
Yokota
DNA Chip Development Center, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
Daisuke
D
Okuzaki
Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Tomoaki
T
Ueda
Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Michiko
M
Ichii
Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Tomohiko
T
Ishibashi
Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Tomomi
T
Isono
Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Yoko
Y
Habuchi
Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Kenji
K
Oritani
Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Yuzuru
Y
Kanakura
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016026:Bone Marrow Transplantation; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000235:genetics*; D002450:Cell Communication / Q000187:drug effects; D004920:Erythropoiesis / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000276:immunology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012156:Reticulocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction
D000964:Antimetabolites, Antineoplastic; D015815:Cell Adhesion Molecules; C428190:Esam protein, mouse; D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D005472:Fluorouracil