Human bone marrow CD34+ progenitor cells mature to T cells on OP9-DL1 stromal cell line without thymus microenvironment

Smedt, Magda De; Hoebeke, Inge; Plum, Jean

doi:10.1016/j.bcmd.2004.08.007

Cited by 110 publications

(101 citation statements)

References 21 publications

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“…The crucial role of Notch signaling in hematopoietic cell fate decisions and T lymphocyte development in particular has been well established (13,16,17). Therefore, we picked up the HZs that contain CD34 high CD43 low HPC and transferred them in toto onto OP9-DL1 monolayers to allow further HPC development and T lineage commitment (Fig.…”

Section: Transfer Of Hzs On Op9-dl1 Cells Generates Early T Lineage Pmentioning

confidence: 99%

Generation of T Cells from Human Embryonic Stem Cell-Derived Hematopoietic Zones

Timmermans

Velghe

Vanwalleghem

et al. 2009

The Journal of Immunology

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181

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Human embryonic stem cells (hESC) are pluripotent stem cells. A major challenge in the field of hESC is the establishment of specific differentiation protocols that drives hESC down a particular lineage fate. So far, attempts to generate T cells from hESC in vitro were unsuccessful. In this study, we show that T cells can be generated in vitro from hESC-derived hematopoietic precursor cells present in hematopoietic zones (HZs). These zones are morphologically similar to blood islands during embryonic development, and are formed when hESC are cultured on OP9 stromal cells.

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Section: Transfer Of Hzs On Op9-dl1 Cells Generates Early T Lineage Pmentioning

confidence: 99%

Generation of T Cells from Human Embryonic Stem Cell-Derived Hematopoietic Zones

Timmermans

Velghe

Vanwalleghem

et al. 2009

The Journal of Immunology

Self Cite

181

151

View full text Add to dashboard Cite

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“…In humans, the role of Notch in T-cell differentiation was evidenced by culturing cord blood or bone marrow CD34 1 progenitors on OP9 stromal cells manipulated to express the Notch ligand DL1 (OP9-DL1 system) [11,12]. The role of Notch in the differentiation of thymic precursors has been mostly addressed by culturing normal or manipulated CD34 1 thymic cells expressing NICD on fetal thymic organ cultures [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Notch ligands potentiate IL‐7‐driven proliferation and survival of human thymocyte precursors

et al. 2009

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Notch and IL-7 are both well-characterized factors involved in T-cell development. In contrast to the mouse model, their precise requirements in the differentiation and/or proliferation of various stages of human thymic development have not been fully explored. Here, we demonstrate that IL-7 alone is sufficient to induce the differentiation of ex vivoimmature single positive (ISP) (sCD3 À CD4 1 CD8 À ) and double positive (DP) (sCD3 À CD4 1 CD8 1 ) human thymic precursors to mature DP expressing sCD3 (sCD3 1 CD4 1 CD8 1 ). We show that activation of Notch signaling by its ligands Delta-1 or Delta-4 potentiates IL-7-driven proliferation and survival of CD34 1 TN and to a lesser extent of CD4 1 ISP precursors. This effect of Notch is related to a sustained induction of IL-7 receptor a chain expression on thymocytes through a decreased methylation of its gene promoter. Thus, we show here that proliferation and differentiation of T-cell precursors are differentially modulated by IL-7 depending on the presence or absence of external signals. These results may have important implications for the clinical use of this cytokine as a strategy aimed at improving immune restoration.

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“…In addition to cytokines, T cell development requires signaling through the Notch receptor, as Notch1 -/-lymphoid progenitors cannot differentiate into DN thymocytes [9]. Conversely, expression of the Notch ligand Delta-Like 1 (DL1) on OP9 cells promotes the differentiation of T cell progenitors, at the expense of the B cell lineage, from a variety of thymic and BM progenitors [10][11][12][13]. An analogous protocol has been developed for NK cell differentiation using IL-2, although whether Notch1 signaling is involved in NK cell development is not known [1,7].…”

Section: Introductionmentioning

confidence: 99%

Transient Notch signaling induces NK cell potential in Pax5‐deficient pro‐B cells

Carotta

Brady

et al. 2006

Eur J Immunol

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Unlike early B/T cell development, NK cell lineage commitment is not well understood, with a major limitation being the lack of a robust culture system to assay NK cell progenitors. Here we have exploited the multi‐lineage potential of Pax5–/– pro‐B cells to establish an effective system to direct differentiation of progenitors into the NK cell lineage. Cultivation of Pax5–/– pro‐B cells on OP9 cells expressing the Notch ligand Delta‐Like1 (OP9‐DL1) in the presence of IL‐7 efficiently induced T and NK cell potential. For NK cells, Notch was only transiently required, as prolonged signaling decreased NK and increased T cell development. Pure NK cell populations could be obtained by the culture of these Notch signal‐experienced cells onto OP9 stroma and IL‐15. A similar transient exposure to Notch was also compatible with the differentiation of NK cells from hematopoietic progenitors, while sustained Notch signaling impaired NK cell generation. Pax5–/– pro‐B cell‐derived NK cells were cytotoxic, secreted cytokines and expressed all the expected NK cell‐specific surface markers examined except the Ly49 family, a phenotype similar to fetal NK cells. These data indicate that Notch signaling induces T/NK cell differentiation in Pax5–/– pro‐B cells that is strikingly similar to early thymopoiesis.

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Human bone marrow CD34+ progenitor cells mature to T cells on OP9-DL1 stromal cell line without thymus microenvironment

Cited by 110 publications

References 21 publications

Generation of T Cells from Human Embryonic Stem Cell-Derived Hematopoietic Zones

Generation of T Cells from Human Embryonic Stem Cell-Derived Hematopoietic Zones

Notch ligands potentiate IL‐7‐driven proliferation and survival of human thymocyte precursors

Transient Notch signaling induces NK cell potential in Pax5‐deficient pro‐B cells

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