Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.148 (Thy1)
 1,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Notch signaling regulates multiple cell fate decisions by hematopoietic precursors. To address whether different amounts of Notch ligand influence lineage choices, we cultured murine bone marrow lin(-)Sca-1(+)c-kit+ cells with increasing densities of immobilized Delta1(ext-IgG) consisting of the extracellular domain of Delta1 fused to the Fc domain of human IgG1. We found that relatively lower densities of Delta1(ext-IgG) enhanced the generation of Sca-1(+)c-kit+ cells, Thy1(+)CD25+ early T cell precursors, and B220(+)CD43(-/lo) cells that, when cocultured with OP9 stroma cells, differentiated into CD19+ early B cell precursors. Higher densities of Delta1(ext-IgG) also enhanced the generation of Sca-1(+)c-kit+ precursor cells and promoted the development of Thy1(+)CD25+ cells, but inhibited the development of B220(+)CD43(-/lo) cells. Analyses of further isolated precursor populations suggested that the enhanced generation of T and B cell precursors resulted from the effects on multipotent rather than lymphoid-committed precursors. The results demonstrate the density-dependent effects of Delta1 on fate decisions of hematopoietic precursors at multiple maturational stages and substantiate the previously unrecognized ability of Delta1 to enhance the development of both early B and T precursor cells.
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PMID:Density of the Notch ligand Delta1 determines generation of B and T cell precursors from hematopoietic stem cells. 1585 88

Bone marrow contains a heterogeneous mixture of mature and maturing precursors of blood cells, progenitor cells for myeloid and lymphoid lineages, and hematopoietic and mesenchymal stem cells. The differentiation potential of these different stem, progenitor, and precursor populations can be evaluated by using transplantation and cell culture assays. In this study, we used a stromal cell co-culture system to evaluate the B and T lineage potential of different subsets of mouse bone marrow. We enriched hematopoietic stem (Lin(-)Sca-1(+)c-kit(+)Thy1.1(low) [Thy1.1(low)]) cells and lymphoid progenitor (Lin(-)Sca-1(+)c-kit(+)Thy1.1(-) [Thy1.1(-)]) cells from mouse bone marrow and co-cultured these populations with OP9 or OP9-DL1 stromal cell lines. Development of the B and T lineages was evaluated over time. Both populations gave rise to B and T cells but with different kinetics. Thy1.1(-) lymphoid progenitors gave rise to B and T lineage cells earlier than did Thy1.1(low) stem cells; and at any given time, percentages of differentiating B and T cells were higher in Thy1.1(-) cultures than in Thy1.1(low) cultures. We also compared the lineage potential of Thy-1.1(-) lymphoid progenitors with that of the recently described common lymphoid progenitor 2 (isolated as Lin(-)Sca-1(+)c-kit(-)Thy1.1(-)B220(+) cells [B220(+)]). B220(+) cells produced B lineage progeny in OP9 cultures more rapidly than did Thy1.1(-) cells and produced higher percentages of differentiating T cells in OP9-DL1 cultures. These studies demonstrate the utility of the OP9 and OP9-DL1 co-culture systems for evaluation of lymphoid lineage potential and for determining the relative position of specific bone marrow populations within the hematopoietic hierarchy.
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PMID:Lymphoid potential of primitive bone marrow progenitors evaluated in vitro. 1595 14

A physiologic role for Notch signaling in hematopoiesis has been clearly defined in lymphoid differentiation, with evidence suggesting a critical role in T-cell versus B-cell fate decisions. Previously, we demonstrated that activation of endogenous Notch receptors by culture of murine lin(-)Sca-1(+)c-kit(+) (LSK) hematopoietic progenitors with exogenously presented Notch ligand, Delta1(ext-IgG), consisting of the extracellular domain of Delta1 fused to the Fc domain of human IgG(1), promoted early T-cell differentiation and increased the number of progenitors capable of short-term lymphoid and myeloid reconstitution. Here we show that culture of LSK precursors with Delta1(ext-IgG) increases the number of progenitors that are able to rapidly repopulate the thymus and accelerate early T-cell reconstitution with a diversified T-cell receptor repertoire. Most of the early T-cell reconstitution originated from cells that expressed lymphoid-associated antigens: B220, Thy1, CD25, and/or IL7Ralpha, whereas the most efficient thymic repopulation on a per cell basis originated from the smaller number of cultured cells that did not express lymphoid-associated antigens. These findings demonstrate the potential of Delta1(ext-IgG)-cultured cells for accelerating early immune reconstitution after hematopoietic cell transplantation.
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PMID:Enhanced T-cell reconstitution by hematopoietic progenitors expanded ex vivo using the Notch ligand Delta1. 1721 87