Abstract
Erythroid Krüppel-like factor (EKLF/KLF1) was identified initially as a critical erythroid-specific transcription factor and was later found to be also expressed in other types of hematopoietic cells, including megakaryocytes and several progenitors. In this study, we have examined the regulatory effects of EKLF on hematopoiesis by comparative analysis of E14.5 fetal livers from wild-type and Eklf gene knockout (KO) mouse embryos. Depletion of EKLF expression greatly changes the populations of different types of hematopoietic cells, including, unexpectedly, the long-term hematopoietic stem cells Flk2− CD34− Lin− Sca1+ c-Kit+ (LSK)-HSC. In an interesting correlation, Eklf is expressed at a relatively high level in multipotent progenitor (MPP). Furthermore, EKLF appears to repress the expression of the colony-stimulating factor 2 receptor β subunit (CSF2RB). As a result, Flk2− CD34− LSK-HSC gains increased differentiation capability upon depletion of EKLF, as demonstrated by the methylcellulose colony formation assay and by serial transplantation experiments in vivo. Together, these data demonstrate the regulation of hematopoiesis in vertebrates by EKLF through its negative regulatory effects on the differentiation of the hematopoietic stem and progenitor cells, including Flk2− CD34− LSK-HSCs.
Highlights
Hematopoiesis is the process in which the hematopoietic/blood system generates multiple types of myeloid and lymphoid blood cells [1,2]
As in the adult bone marrow, the mouse fetal liver blood system consists of multiple lineages, with the lymphoid lineage leading to T, B, and natural killer (NK) cells while the megakaryocyte, erythrocytes, granulocyte, and monocyte-macrophage belong to myeloid lineage
Lymphoid and myeloid lineage commitment occurs in multipotent hematopoietic progenitors, including the multipotent progenitor (MPP), the common myeloid progenitor (CMP), the myeloid/erythroid progenitor (MEP), the granulocyte/macrophage progenitor (GMP), and the common lymphoid progenitor (CLP), with MPP generated through self-renewal and differentiation of hematopoietic stem cells (HSC) [5,6,7,8,9]
Summary
Hematopoiesis is the process in which the hematopoietic/blood system generates multiple types of myeloid and lymphoid blood cells [1,2]. As in the adult bone marrow, the mouse fetal liver blood system consists of multiple lineages, with the lymphoid lineage leading to T, B, and natural killer (NK) cells while the megakaryocyte, erythrocytes, granulocyte, and monocyte-macrophage belong to myeloid lineage. How extensively, EKLF participates in the regulation of hematopoiesis, other than the megakaryocyte–erythrocyte separation and monocyte-to-macrophage [30], has remained unknown In this communication, we report that EKLF is expressed in LT-HSCs as defined by the marker set Flk2− CD34− Lin− Sca1+ Kit+ (LSK) [12], which we term as Flk2-CD34-HSC throughout the studies below. These findings establish EKLF as a hierarchical regulator of hematopoiesis in mammals, as suggested by the study of mouse fetal hematopoiesis shown below
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