Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Restricted Dendritic Cell and Monocyte Progenitors in Human Cord Blood and Bone Marrow

ABSTRACT: In mice, two restricted DC progenitors, macrophage-dendritic progenitor (MDP) and common dendritic cell progenitor (CDP) demonstrate increasing commitment of DC lineage as they sequentially lose granulocyte and monocyte potential respectively. Identifying these progenitors has enabled understanding of the role of DCs and monocytes in immunity and tolerance in mice. In humans, however, restricted monocyte and DC progenitors remain unknown. Progress in studying human DC development has been hampered by lack of an in vitro culture system that recapitulates in vivo DC hematopoiesis. Here we report a culture system that supports development of CD34+ hematopoietic stem cell progenitors into the three major human DC subsets, monocytes, granulocytes, NK and B cells. Using this culture system we defined the pathway for human DC development, and revealed the sequential origin of human DCs from increasingly restricted progenitors: a granulocyte-monocyte-DC progenitor (hGMDP) that develops into a monocyte-DC progenitor (hMDP) that develops into monocytes and a common DC progenitor (hCDP) that is restricted to produce the three major DC subsets. The phenotype of the DC progenitors partially overlaps with granulocyte monocyte progenitors (GMPs). These progenitors reside in human cord blood and bone marrow but not in the blood or lymphoid tissues in the steady state. We performed whole transcriptome expression analysis on monocytes and subsets of dendritic cells i.e. CD1c+ DCs, CD141+ DCs and CD303+ pDCs isolated from blood or differentiated in culture from cord blood CD34+ cells in presence of MS5 stromal cells and Flt3l, GM-CSF and SCF cytokines.

ORGANISM(S): Homo sapiens

SUBMITTER: Peter Wilkinson

PROVIDER: E-GEOD-65128 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Transcriptional profiling of mouse comparing in vitro-derived DC progenitors from control and Gata2 conditional knockout mice. Two-condition experiment, Control DCs vs. G2 Knockout DCs. Biological replicates: 4 control, 3 Gata2 knockout, independently grown and harvested. One replicate per array. Dendritic cells (DCs) are critical immune response regulators; however, the mechanism of DC differentiation is not fully understood. Heterozygous germline GATA2 mutations induce GATA2 deficiency syndrome, characterized by monocytopenia, a predisposition to myelodysplasia/acute myeloid leukemia, and a profoundly reduced DC population, which is associated with increased susceptibility to viral infections, impaired phagocytosis, and decreased cytokine production. To define the role of GATA2 in DC differentiation and function, we studied Gata2 conditional knockout and haploinsufficient mice. Gata2 conditional deficiency significantly reduced the DC count, whereas Gata2 haploinsufficiency did not affect this population. GATA2 was required for the in vitro generation of DCs from Linâ??Sca-1+Kit+ cells, common myeloid-restricted progenitors, and common dendritic cell precursors, but not common lymphoid-restricted progenitors or granulocyte-macrophage progenitors, suggesting that GATA2 functions in the myeloid pathway of DC differentiation. Moreover, expression profiling demonstrated reduced expression of myeloid-related genes, including mafb, and increased expression of T-lymphocyte-related genes, including Gata3 and Tcf7, in Gata2-deficient DC progenitors. In addition, GATA2 was found to bind an enhancer element 190-kb downstream region of Gata3, and a reporter assay exhibited significantly reduced luciferase activity after adding this enhancer region to the Gata3 promoter, which was recovered by GATA sequence deletion within Gata3 +190. These results suggest that GATA2 plays an important role in cell fate specification toward the myeloid versus T lymphocyte lineage by regulating lineage-specific transcription factors in DC progenitors, thereby contributing to DC differentiation.

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Restricted Dendritic Cell and Monocyte Progenitors in Human Cord Blood and Bone Marrow

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