Notch and lymphopoiesis: a view from the microenvironment

Parreira, Leonor; Neves, Hélia; Simões, Sérgio

doi:10.1016/s1044-5323(03)00004-6

Cited by 22 publications

(18 citation statements)

References 57 publications

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“…36,37 The use of different Notch ligand-receptor combinations may induce Notch signals of different strength, particularly in the presence of intrinsic or extrinsic Notch modulators. Moreover, the restricted patterns of expression of Notch ligands throughout the hematopoietic system might reflect physiologically important effects of individual Notch ligands, whereby the expression of Jagged1 in the stem cell niche within the marrow is thought supportive of stem cell renewal and early precursor development, whereas the expression of relatively high amounts of Delta1 in the thymus may be important both for promotion of T cell development as well as for inhibiting myeloid development.…”

Section: Discussionmentioning

confidence: 99%

Dose-dependent effects of the Notch ligand Delta1 on ex vivo differentiation and in vivo marrow repopulating ability of cord blood cells

Delaney

Varnum‐Finney

Aoyama

et al. 2005

Blood

250

201

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IntroductionThe widespread expression of Notch family members by hematopoietic cells, including stem cells, has led to speculation about their role in hematopoiesis. A critical role for Notch signaling in T versus B cell-fate decisions has been established in vivo with gain-and loss-of-function studies. 1-3 Despite profound effects on lymphoid cell fates, these studies have failed to identify significant effects on myeloid differentiation. However, in contrast to these in vivo studies, in vitro studies in which the constitutively active intracellular domain of Notch1 was overexpressed did reveal inhibition of myeloid differentiation and enhanced generation of precursor cells in addition to promotion of early T-cell differentiation, indicating a potential role of Notch signaling on multipotent precursor cells. [4][5][6][7] To exploit Notch signaling as a means of directing desired cell-fate outcomes or generating precursor cells from nontransduced stem cells, soluble or cell-expressed Notch ligands have been used by a number of laboratories. Initial studies met with only modest success, resulting in only a few-fold increase in progenitor cell number, 4,5,[7][8][9][10][11][12] but our more recent studies using an engineered Notch ligand Delta1 in immobilized form demonstrated profound effects on murine precursors with a multilog increase in the number of Sca-1 ϩ c-kit ϩ precursors with short-term lymphoid and myeloid repopulating ability. 7 Based on these findings, we examined Notch signaling in human cord blood precursors because inadequate stem cell numbers in cord blood grafts have been associated with significantly delayed engraftment and, as a result, increased early transplant-related mortality from infection, thereby limiting the use of cord blood for hematopoietic cell transplantation (HCT) in adults and larger children. Our studies demonstrated an increase in early human hematopoietic reconstitution in NOD/SCID mice, indicating potential clinical importance in overcoming the delayed engraftment in umbilical cord blood transplants. 5 We investigated whether quantitative differences in ligandinduced activation of Notch signaling could be the basis for the reported variability with Notch activation and cell fate outcomes of hematopoietic precursors and whether such quantitative differences might determine whether precursors self-renew or adopt a lymphoid cell fate. The importance of quantitative aspects of Notch signaling has been shown in Drosophila where different functions of Notch can require different thresholds of signaling. For example, Notch haploinsufficiency suffices to perform most functions of Notch indistinguishably from wild type, but causes improper specification of the dorsoventral margin of the wing, giving rise to the eponymous "notched wing" phenotype. 13,14 In mammals, a reduction in Notch1 gene dosage in developing T cells favors the ␥␦ T-cell fate over the ␣␤ T-cell fate, 15 and a dose-dependent effect of Delta1 on the determination of type 1 helper T cell (Th1) versus Th2 cell-fate dec...

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Section: Discussionmentioning

confidence: 99%

Dose-dependent effects of the Notch ligand Delta1 on ex vivo differentiation and in vivo marrow repopulating ability of cord blood cells

Delaney

Varnum‐Finney

Aoyama

et al. 2005

Blood

250

201

View full text Add to dashboard Cite

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“…Interestingly, while thymic epithelial cells express high levels of Dll-1 (20,21), bone marrow stroma does not (19), although the levels of Dll-1 to which progenitors are exposed in the thymus, vs various niches within the bone marrow, remains unresolved. In this study, we demonstrate that OP9-DL1 cells inhibit myelopoiesis from HPCs, in contrast to OP9-control cells (23).…”

Section: Discussionmentioning

confidence: 99%

“…In fact, HPCs are rapidly induced to commit to non-T cell fates in the OP9 stromal cell environment (18). Interestingly, neither OP9 cells nor bone marrow stroma express detectable levels of Dll-1 (19), in sharp contrast to the high levels of Dll-1 expression found on thymic epithelial cells (20,21). We have recently demonstrated that when OP9 cells are retrovirally transduced to express Dll-1 (OP9-DL1 cells), they support T, but no longer B, lymphopoiesis from HPCs (22,23).…”

mentioning

confidence: 99%

Notch Signaling Requires GATA-2 to Inhibit Myelopoiesis from Embryonic Stem Cells and Primary Hemopoietic Progenitors

Pooter

Schmitt

Pompa

et al. 2006

The Journal of Immunology

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The bone marrow and thymus, although both hemopoietic environments, induce very distinct differentiation outcomes. The former supports hemopoietic stem cell self-renewal and multiple hemopoietic lineages, while the latter supports T lymphopoiesis almost exclusively. This distinction suggests that the thymic environment acts to restrict the hemopoietic fates available to thymic immigrants. In this study, we demonstrate that the addition of the Notch ligand Delta-like-1 (Dll-1) to an in vitro system that otherwise supports myelopoiesis, greatly reduces the myelopoietic potential of stem cells or uncommitted progenitors. In contrast, committed myeloid progenitors mature regardless of the presence of Dll-1. The block in myelopoiesis is the direct result of Notch signaling within the hemopoietic progenitor, and Dll-1-induced signals cause a rapid increase in the expression of the zinc finger transcription factor GATA-2. Importantly, in the absence of GATA-2, Dll-1-induced signals fail to inhibit commitment to the myeloid fate. Taken together, our results support a role for GATA-2 in allowing Dll-1 to restrict non-T cell lineage differentiation outcomes.

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“…Different Notch molecules (mammalian cells contain four Notch molecules, Notch-1 to -4) and their ligands (Jagged-1 and -2 and Delta-1, -3, and -4) are expressed in diverse cell types, including endothelial cells (55,65) and B cells (6,48), the two host cells for KSHV infection. Studies have suggested that Notch signals are involved in endothelial cell differentiation and B-cell development (5,28,48,50). Therefore, it is possible that the Notch molecules in these cells can be activated by local signals and thus induce the expression of the K14/vGPCR transcript.…”

Section: Discussionmentioning

confidence: 99%

RBP-J (CSL) Is Essential for Activation of the K14/vGPCR Promoter of Kaposi's Sarcoma-Associated Herpesvirus by the Lytic Switch Protein RTA

Liang

Ganem

2004

J Virol

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Notch and lymphopoiesis: a view from the microenvironment

Cited by 22 publications

References 57 publications

Dose-dependent effects of the Notch ligand Delta1 on ex vivo differentiation and in vivo marrow repopulating ability of cord blood cells

Dose-dependent effects of the Notch ligand Delta1 on ex vivo differentiation and in vivo marrow repopulating ability of cord blood cells

Notch Signaling Requires GATA-2 to Inhibit Myelopoiesis from Embryonic Stem Cells and Primary Hemopoietic Progenitors

RBP-J (CSL) Is Essential for Activation of the K14/vGPCR Promoter of Kaposi's Sarcoma-Associated Herpesvirus by the Lytic Switch Protein RTA

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