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Growth factor independence 1 (Gfi1) regulates cell-fate decision of a bipotential granulocytic-monocytic precursor defined by expression of Gfi1 and CD48.

ABSTRACT: The transcriptional repressor Gfi1 regulates the expression of genes important for survival, proliferation and differentiation of hematopoietic cells. Gfi1 deficient mice are severely neutropenic and accumulate ill-defined CD11b(+)GR1(int) myeloid cells. Here we show that Gfi1 expression levels determine mono- or granulocytic lineage choice in precursor cells. In addition, we identify CD48 as a cell surface marker which enables a better definition of monocytes and granulocytes in mouse bone marrow. Using the CD48/Gr1/Gfi1 marker combination we can show that the CD11b(+)GR1(int) cells accumulating in Gfi1 deficient mice are monocytes and not granulocyte precursors. Expression of CD48, Gr1 and Gfi1 define different bone marrow subpopulations that are either committed to the granulocytic lineage, or bipotential precursors of granulocytes or monocytes. Finally, a comparison of genes differentially expressed between murine Gfi1 high granulocytic precursors and mature granulocytes with gene expression changes from human myeloblasts versus neutrophils show a strong resemblance of human and mouse differentiation pathways. This underlines the value of the markers CD48 and Gfi1 identified here to study human and murine granulo-monocytic differentiation.

SUBMITTER: Vassen L

PROVIDER: S-EPMC3512177 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Mutations in the CCAAT enhancer binding protein epsilon (C/EBPepsilon) gene have been identified in the cells of patients with neutrophil specific granule deficiency, a rare congenital disorder marked by recurrent bacterial infections. Their neutrophils, in addition to lacking specific granules required for normal respiratory burst activity, also lack normal phagocytosis and chemotaxis. Although the specific granule deficiency phenotype has been replicated in C/EBPepsilon(-/-) (knockout [KO]) mice, the mechanisms by which C/EBPepsilon mutations act to decrease neutrophil function are not entirely clear.In order to determine the role of C/EBPepsilon in neutrophil differentiation and migration, we generated immortalized progenitor cell lines from C/EBPepsilon KO and wild-type mice and performed expression and flow cytometric analysis and functional studies.Expression of lineage-specific cell surface antigens on our in vitro differentiated cell lines revealed persistent expression of monocytic markers on KO granulocytes. We verified this in primary murine peripheral blood and bone marrow cells. In addition, KO bone marrow had an increase in immature myeloid precursors at the common myeloid progenitor and granulocyte/monocyte progenitor levels, suggesting a critical role for C/EBPepsilon not only in granulocyte maturation beyond the promyelocyte stage, but also in the monocyte/granulocyte lineage decision. We found that restoration of Hlx (H2.0-like homeo box 1) expression, which was decreased in C/EBPepsilon KO cells, rescued chemotaxis, but not the other defects of C/EBPepsilon KO neutrophils.We show two new regulatory functions of C/EBPepsilon in myelopoiesis: in the absence of C/EBPepsilon, there is not only incomplete differentiation of granulocytes, but myelopoiesis is disrupted with the appearance of an intermediate cell type with monocyte and granulocyte features, and the neutrophils have abnormal chemotaxis. Restoration of expression of Hlx provides partial recovery of function; it has no effect on neutrophil maturation, but can completely ameliorate the chemotaxis defect in C/EBPepsilon KO cells.

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Growth factor independence 1 (Gfi1) regulates cell-fate decision of a bipotential granulocytic-monocytic precursor defined by expression of Gfi1 and CD48.

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