Abstract
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.
Highlights
Numerous hematopoietic cells are perpetually generated from hematopoietic stem/progenitor cells that exist primarily in the bone marrow (BM) after birth
We previously reported that endothelial cell-selective adhesion molecule (ESAM) expression is a biomarker of hematopoietic stem cells (HSCs) in mice and is useful to trace the activation of HSCs upon BM injury [7, 8]
These results suggested that erythropoiesis dysfunction, after BM injury, is a prominent phenotype in ESAM-KO mice
Summary
Numerous hematopoietic cells are perpetually generated from hematopoietic stem/progenitor cells that exist primarily in the bone marrow (BM) after birth. An increase in erythropoiesis is required in times of stress, 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. 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]
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